Cardiac sarcomere inhibitors

ABSTRACT

Provided are compounds of Formula (I): 
                         
or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2A , R 2B , R 3 , R 4 , and R 5  are as defined herein. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/726,162, filed Aug. 31, 2018, entitled “CARDIAC SARCOMEREINHIBITORS,” the contents of which are hereby incorporated by referencein their entirety for all purposes.

FIELD

Provided herein are heterocyclic compounds, pharmaceutical compositionscomprising such compounds, and methods of treating various cardiacdiseases and conditions with such compounds.

BACKGROUND

The disclosure relates to certain chemical entities that selectivelymodulate the cardiac sarcomere, and specifically to certain chemicalentities, pharmaceutical compositions and methods for treating variouscardiac diseases and conditions.

The cardiac sarcomere is composed of a network of contractile andstructural proteins that regulate cardiac muscle function. Thecomponents of the cardiac sarcomere present targets for the treatment ofvarious cardiac diseases and conditions, for example by increasingcontractility or facilitating complete relaxation to modulate systolicand diastolic function, respectively. The force and speed of cardiacmuscle contraction is a major determinant of organ function and ismodulated by the cyclical interactions of actin and myosin. Regulationof actin and myosin binding is determined by a network of myofilamentregulatory proteins and the level of intracellular Ca²⁺. The troponincomplex and tropomyosin are thin filament proteins which govern theavailability of actin binding sites, and the essential and regulatorylight chains, and myosin binding protein C modulate the position andmechanical properties of myosin.

Abnormalities in the cardiac sarcomere have been identified as thedriving cause for a variety of cardiac diseases and conditions, such ashypertrophic cardiomyopathy (HCM) and heart failure with preservedejection fraction (HFpEF). Mutations in the proteins of the sarcomerecause disease by rendering the cardiac muscle either ‘hyper’ or ‘hypo’contractile. Modulators of the cardiac sarcomere can be used torebalance contractility and stop or reverse the course of disease.

Current agents that target the cardiac sarcomere, such as inotropes(drugs that increase the contractile ability of the heart) are poorlyselective for cardiac tissue, which leads to recognized adverse effectsthat limit their use. These adverse effects include cell damage causedby an increased rate of energy expenditure, exacerbation of relaxationabnormalities, and potential arrhythmogenic side effects that may resultfrom increased cytosolic Ca²⁺ and cyclic AMP concentrations in theinotropically stimulated myocardium. Given the limitations of currentagents, new approaches are needed to improve cardiac function in HCM andHFpEF.

There remains a great need for agents that exploit new mechanisms ofaction and may have better outcomes in terms of relief of symptoms,safety, and patient mortality, both short-term and long-term. New agentswith an improved therapeutic index over current agents will provide ameans to achieve these clinical outcomes. The selectivity of agentsdirected at the cardiac sarcomere (for example, by targeting cardiacmyosin) has been identified as an important means to achieve thisimproved therapeutic index. The present disclosure provides such agents(particularly cardiac sarcomere inhibitors) and methods for their use.These agents are allosteric inhibitors of cardiac myosin. Benefits ofthese compounds include a wider therapeutic index, less impact oncardiac relaxation, better pharmacokinetics, and better safety.

The present disclosure provides chemical entities, pharmaceuticalcompositions and methods for the treatment of heart failure includingHCM and HFpEF. The compositions are inhibitors of the cardiac sarcomere,for example, inhibitors of cardiac myosin.

BRIEF SUMMARY

In one aspect, provided is a compound of Formula (I), or apharmaceutically acceptable salt thereof:

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedphenyl and substituted or unsubstituted pyridyl;

R^(2A), R^(2B), and R³ are defined by any one of (i)-(iii):

-   -   (i) R^(2A) is H or substituted or unsubstituted alkyl;        -   R^(2B) is selected from the group consisting of H,            substituted or unsubstituted alkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted cycloalkenyl, substituted or unsubstituted            cycloalkynyl, substituted or unsubstituted heterocyclyl,            substituted or unsubstituted aryl, and substituted or            unsubstituted heteroaryl; and        -   R³ is substituted or unsubstituted phenyl or substituted or            unsubstituted pyridyl;    -   or    -   (ii) R^(2A) is H or substituted or unsubstituted alkyl;        -   R^(2B) is substituted or unsubstituted phenyl or substituted            or unsubstituted pyridyl; and        -   R³ is substituted or unsubstituted alkyl;    -   or    -   (iii) R^(2A) and R^(2B) are taken together with the carbon atom        to which they are attached to form G¹, wherein G¹ is a        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted cycloalkenyl, substituted or unsubstituted        cycloalkynyl, or substituted or unsubstituted heterocyclyl ring,        each of which is optionally fused to a phenyl ring; and        -   R³ is selected from the group consisting of substituted or            unsubstituted alkyl, substituted or unsubstituted alkenyl,            substituted or unsubstituted alkynyl, substituted or            unsubstituted cycloalkyl, substituted or unsubstituted            cycloalkenyl, substituted or unsubstituted cycloalkynyl,            substituted or unsubstituted heterocyclyl, substituted or            unsubstituted aryl, and substituted or unsubstituted            heteroaryl;

R⁴ is H or substituted or unsubstituted alkyl; and

R⁵ is H or substituted or unsubstituted alkyl;

wherein, when one or more of provisions (a)-(c) apply, then R¹ issubstituted or unsubstituted pyridyl or phenyl substituted with at leastone substituent other than methyl or methoxy:

-   -   (a) R^(2A) and R^(2B) are as defined by (i) and R³ is        substituted or unsubstituted phenyl;    -   (b) R^(2A) and R³ are as defined by (ii) and R^(2B) is        4-methoxyphenyl;    -   (c) R^(2A), and R^(2B)— are as defined by (iii) and R³ is        4-methoxyphenylmethyl.

In another aspect, provided is a compound of Formula (Ia), or apharmaceutically acceptable salt thereof:

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedphenyl and substituted or unsubstituted pyridyl;

R^(2A) is H or substituted or unsubstituted alkyl;

R^(2B) is selected from the group consisting of H, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkynyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl;

R³ is substituted or unsubstituted phenyl or substituted orunsubstituted pyridyl;

R⁴ is H or substituted or unsubstituted alkyl; and

R⁵ is H or substituted or unsubstituted alkyl;

wherein, when R³ is substituted or unsubstituted phenyl, R¹ issubstituted or unsubstituted pyridyl or phenyl substituted with at leastone substituent other than methyl or methoxy.

In another aspect, provided is a compound of Formula (Ib), or apharmaceutically acceptable salt thereof:

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedphenyl and substituted or unsubstituted pyridyl;

R^(2A) is H or substituted or unsubstituted alkyl;

R^(2B) is substituted or unsubstituted phenyl or substituted orunsubstituted pyridyl;

R³ is substituted or unsubstituted alkyl;

R⁴ is H or substituted or unsubstituted alkyl; and

R⁵ is H or substituted or unsubstituted alkyl;

wherein, when R^(2B) is 4-methoxyphenyl, R¹ is substituted orunsubstituted pyridyl or phenyl substituted with at least onesubstituent other than methyl or methoxy.

In another aspect, provided is a compound of Formula (Ic), or apharmaceutically acceptable salt thereof:

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedpyridyl and substituted or unsubstituted pyridyl;

R^(2A) and R^(2B) are taken together with the carbon atom to which theyare attached to form G¹, wherein G¹ is a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl, substituted orunsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclylring, each of which is optionally fused to a phenyl ring;

R³ is selected from the group consisting of substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkynyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl;

R⁴ is H or substituted or unsubstituted alkyl; and

R⁵ is H or substituted or unsubstituted alkyl;

wherein, when R³ is 4-methoxyphenylmethyl, R¹ is substituted orunsubstituted pyridyl or phenyl substituted with at least onesubstituent other than methyl or methoxy.

In another aspect, provided is a compound of Formula (Id), or apharmaceutically acceptable salt thereof:

wherein:

R^(2A) is H or substituted or unsubstituted alkyl;

R^(2B) is selected from the group consisting of H, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkynyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl;

n is 0, 1, or 2;

R^(3a) is selected from the group consisting of halo and cyano; and

R⁴ is H.

In another aspect, provided is a compound of Formula (Ie), or apharmaceutically acceptable salt thereof:

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedphenyl and substituted or unsubstituted pyridyl;

R^(2A) is H or substituted or unsubstituted alkyl;

R^(2B) is substituted or unsubstituted phenyl or substituted orunsubstituted pyridyl; and

R⁴ is H;

wherein, when R^(2B) is 4-methoxyphenyl, R¹ is substituted orunsubstituted pyridyl or phenyl substituted with at least onesubstituent other than methyl or methoxy.

In another aspect, provided is a compound of Formula (If), or apharmaceutically acceptable salt thereof:

wherein:

G¹ is selected from the group consisting of substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl, substituted orunsubstituted cycloalkynyl, and substituted or unsubstitutedheterocyclyl ring, each of which is optionally fused to a phenyl ring;

R^(1a) is selected from the group consisting of cyano, halo, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkyl, andsubstituted or unsubstituted heterocyclyl;

R^(2a) is selected from the group consisting of substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl,substituted or unsubstituted acyl, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted aminocarbonylamino, andsubstituted or unsubstituted alkyl;

n is 0, 1, 2, or 3;

R³ is selected from the group consisting of substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, and substituted or unsubstituted aryl; and

R⁴ is H;

wherein, when R³ is 4-methoxyphenylmethyl, R^(1a) is not methyl ormethoxy.

In another aspect, provided is a compound of Formula (Ig), or apharmaceutically acceptable salt thereof:

wherein:

R^(1a) is selected from the group consisting of cyano, halo, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkyl, andsubstituted or unsubstituted heterocyclyl;

R^(2a) is selected from the group consisting of substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl,substituted or unsubstituted acyl, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted aminocarbonylamino, andsubstituted or unsubstituted alkyl;

n is 0, 1, 2, or 3;

R^(1a) is selected from the group consisting of halo and cyano; and R⁴is H.

In another aspect, provided is a compound of Formula (Ih), or apharmaceutically acceptable salt thereof:

wherein:

R^(1a) is selected from the group consisting of cyano, halo, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkyl, andsubstituted or unsubstituted heterocyclyl;

R^(2a) is selected from the group consisting of substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl,substituted or unsubstituted acyl, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted aminocarbonylamino, andsubstituted or unsubstituted alkyl;

R³ is selected from the group consisting of substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, and substituted or unsubstituted aryl; and

R⁴ is H;

wherein, when R³ is 4-methoxyphenylmethyl, R^(1a) is not methyl ormethoxy.

In another aspect, provided is a compound of Formula (Ii), or apharmaceutically acceptable salt thereof:

wherein:

R^(1a) is selected from the group consisting of cyano, halo, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkyl, andsubstituted or unsubstituted heterocyclyl;

R^(2a) is selected from the group consisting of substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl,substituted or unsubstituted acyl, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted aminocarbonylamino, andsubstituted or unsubstituted alkyl;

R³ is selected from the group consisting of substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, and substituted or unsubstituted aryl;

R⁴ is H;

R⁵ is H or substituted or unsubstituted alkyl; and

X is —CH₂— or —C(O)—;

wherein, when R³ is 4-methoxyphenylmethyl, R^(1a) is not methyl ormethoxy.

In another aspect, provided is a compound of Formula (Ij), or apharmaceutically acceptable salt thereof:

wherein:

R¹ is substituted or unsubstituted phenyl;

each R^(2b) is independently substituted or unsubstituted alkyl;

R³ is substituted or unsubstituted phenyl or substituted orunsubstituted pyridyl;

R⁴ is H;

R⁵ is H or substituted or unsubstituted alkyl;

n is 0, 1, or 2; and

q is 0 or 1,

wherein, when R³ is substituted or unsubstituted phenyl, then R′ isphenyl substituted with at least one substituent other than methyl ormethoxy.

In another aspect, provided is a compound of Formula (Ik-1), or apharmaceutically acceptable salt thereof:

wherein:

R^(2A) is H or substituted or unsubstituted alkyl;

R^(2B) is selected from the group consisting of substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl, andsubstituted or unsubstituted heterocyclyl;

m is 0, 1, or 2;

p is 0, 1, or 2;

each R^(1a) is independently selected from the group consisting of haloand substituted or unsubstituted alkyl;

each R^(1a) is independently selected from the group consisting of halo,cyano, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, and substituted or unsubstituted alkoxy; and

R⁴ is H.

In another aspect, provided is a compound of Formula (Ik-2), or apharmaceutically acceptable salt thereof:

wherein:

G¹ is selected from the group consisting of substituted or unsubstitutedcycloalkyl and substituted or unsubstituted heterocyclyl;

each R^(1a) is independently selected from the group consisting of haloand substituted or unsubstituted alkyl;

each R^(2a) is independently selected from the group consisting ofsubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted aminoacyl, substituted or unsubstituted acyl, substitutedor unsubstituted aminothionyl, substituted or unsubstitutedaminocarbonylamino, and substituted or unsubstituted alkyl;

each R^(3a) is independently selected from the group consisting of halo,cyano, and substituted or unsubstituted alkyl,

R⁴ is H;

R⁵ is H or substituted or unsubstituted alkyl;

m is 0, 1, or 2;

n is 0, 1, or 2; and

p is 0, 1, or 2.

In another aspect, provided is a compound of Formula (Il), or apharmaceutically acceptable salt thereof:

wherein:

R^(2A) is H or substituted or unsubstituted alkyl;

R^(2b) is selected from the group consisting of H, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl,substituted or unsubstituted aminoacyl, and hydroxy;

m is 0, 1, or 2;

p is 0, 1, or 2;

each R^(1a) is independently selected from the group consisting of haloand substituted or unsubstituted alkyl;

each R^(1a) is independently halo; and

R⁴ is H.

In another aspect, provided is a compound of Formula (Im), or apharmaceutically acceptable salt thereof:

wherein:

Q is —O— or —N(R^(2b))—;

R^(2b) is selected from the group consisting of H and substituted orunsubstituted acyl;

m is 0, 1, or 2;

p is 0, 1, or 2;

each R^(1a) is independently selected from the group consisting of haloand substituted or unsubstituted alkyl;

each R^(1a) is independently halo; and

R⁴ is H.

In another aspect, provided is a compound of Formula (In-1), or apharmaceutically acceptable salt thereof:

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedphenyl and substituted or unsubstituted pyridyl;

R^(2A), R^(2B), and R³ are defined by any one of (i)-(iii):

-   -   (i) R^(2A) is H or substituted or unsubstituted alkyl;        -   R^(2B) is selected from the group consisting of H,            substituted or unsubstituted alkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted cycloalkenyl, substituted or unsubstituted            cycloalkynyl, substituted or unsubstituted heterocyclyl,            substituted or unsubstituted aryl, and substituted or            unsubstituted heteroaryl; and        -   R³ is substituted or unsubstituted phenyl or substituted or            unsubstituted pyridyl;    -   or    -   (ii) R^(2A) is H or substituted or unsubstituted alkyl;        -   R^(2B) is substituted or unsubstituted phenyl or substituted            or unsubstituted pyridyl; and        -   R³ is substituted or unsubstituted alkyl;    -   or    -   (iii) R^(2A) and R^(2B) are taken together with the carbon atom        to which they are attached to form G¹, wherein G¹ is a        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted cycloalkenyl, substituted or unsubstituted        cycloalkynyl, or substituted or unsubstituted heterocyclyl ring,        each of which is optionally fused to a phenyl ring; and        -   R³ is selected from the group consisting of substituted or            unsubstituted alkyl, substituted or unsubstituted alkenyl,            substituted or unsubstituted alkynyl, substituted or            unsubstituted cycloalkyl, substituted or unsubstituted            cycloalkenyl, substituted or unsubstituted cycloalkynyl,            substituted or unsubstituted heterocyclyl, substituted or            unsubstituted aryl, and substituted or unsubstituted            heteroaryl;    -   R⁴ is H or substituted or unsubstituted alkyl; and    -   R⁵ is H or substituted or unsubstituted alkyl;        wherein, when one or more of provisions (a)-(c) apply, then R¹        is substituted or unsubstituted pyridyl or phenyl substituted        with at least one substituent other than methyl or methoxy:    -   (a) R^(2A) and R^(2B) are as defined by (i) and R³ is        substituted or unsubstituted phenyl;    -   (b) R^(2A) and R³ are as defined by (ii) and R^(2B) is        4-methoxyphenyl;    -   (c) R^(2A), and R^(2B)— are as defined by (iii) and R³ is        4-methoxyphenylmethyl.

In another aspect, provided is a compound of Formula (In-2), or apharmaceutically acceptable salt thereof:

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedphenyl and substituted or unsubstituted pyridyl;

R^(2A), R^(2B), and R³ are defined by any one of (i)-(iii):

-   -   (i) R^(2A) is H or substituted or unsubstituted alkyl;        -   R^(2B) is selected from the group consisting of H,            substituted or unsubstituted alkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted cycloalkenyl, substituted or unsubstituted            cycloalkynyl, substituted or unsubstituted heterocyclyl,            substituted or unsubstituted aryl, and substituted or            unsubstituted heteroaryl; and        -   R³ is substituted or unsubstituted phenyl or substituted or            unsubstituted pyridyl;    -   or    -   (ii) R^(2A) is H or substituted or unsubstituted alkyl;        -   R^(2B) is substituted or unsubstituted phenyl or substituted            or unsubstituted pyridyl; and        -   R³ is substituted or unsubstituted alkyl;    -   or    -   (iii) R^(2A) and R^(2B) are taken together with the carbon atom        to which they are attached to form G¹, wherein G¹ is a        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted cycloalkenyl, substituted or unsubstituted        cycloalkynyl, or substituted or unsubstituted heterocyclyl ring,        each of which is optionally fused to a phenyl ring; and        -   R³ is selected from the group consisting of substituted or            unsubstituted alkyl, substituted or unsubstituted alkenyl,            substituted or unsubstituted alkynyl, substituted or            unsubstituted cycloalkyl, substituted or unsubstituted            cycloalkenyl, substituted or unsubstituted cycloalkynyl,            substituted or unsubstituted heterocyclyl, substituted or            unsubstituted aryl, and substituted or unsubstituted            heteroaryl;

R⁴ is H or substituted or unsubstituted alkyl; and

R⁵ is H or substituted or unsubstituted alkyl;

wherein, when one or more of provisions (a)-(c) apply, then R¹ issubstituted or unsubstituted pyridyl or phenyl substituted with at leastone substituent other than methyl or methoxy:

-   -   (a) R^(2A) and R^(2B) are as defined by (i) and R³ is        substituted or unsubstituted phenyl;    -   (b) R^(2A) and R³ are as defined by (ii) and R^(2B) is        4-methoxyphenyl;    -   (c) R^(2A), and R^(2B)— are as defined by (iii) and R³ is        4-methoxyphenylmethyl.

Provided in some embodiments are compounds selected from the groupconsisting of compounds of Table 1, or a pharmaceutically acceptablesalt thereof.

Provided in some aspects is a pharmaceutical composition containing acompound of Formula (I) or any variation thereof, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

Provided in some aspects are methods of treating heart disease in asubject in need thereof, the method comprising administering to thesubject a compound of Formula (I) or any variation thereof, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition containing a compound of Formula (I) or any variationthereof or a pharmaceutically acceptable salt thereof. In someembodiments, the heart disease is hypertrophic cardiomyopathy (HCM). Insome embodiments, the HCM is obstructive or nonobstructive or is causedby sarcomeric and/or non-sarcomeric mutations. In some embodiments, theheart disease is heart failure with preserved ejection fraction (HFpEF).In some embodiments, the heart disease is selected from the groupconsisting of diastolic dysfunction, primary or secondary restrictivecardiomyopathy, myocardial infarction, angina pectoris, and leftventricular outflow tract obstruction. In some embodiments, the heartdisease is hypertensive heart disease, congenital heart disease, cardiacischemia, coronary heart disease, diabetic heart disease, congestiveheart failure, right heart failure, cardiorenal syndrome, orinfiltrative cardiomyopathy. In some embodiments, the heart disease is acondition that is or is related to cardiac senescence and/or diastolicdysfunction due to aging. In some embodiments, the heart disease is acondition that is or is related to left ventricular hypertrophy and/orconcentric left ventricular remodeling.

Provided in other aspects are methods of treating a disease or conditionassociated with HCM in a subject in need thereof, wherein the methodcomprises administering to the subject a compound of Formula (I) or anyvariation thereof, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition containing a compound of Formula (I) or anyvariation thereof or a pharmaceutically acceptable salt thereof. In someembodiments, the disease or condition is selected from the groupconsisting of Fabry's Disease, Danon Disease, mitochondrialcardiomyopathies, and Noonan Syndrome.

Provided in some aspects are methods of treating a disease or conditionthat is associated with secondary left ventricular wall thickening in asubject in need thereof, wherein the method comprises administering tothe subject a compound of Formula (I) or any variation thereof, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition containing a compound of Formula (I) or any variationthereof or a pharmaceutically acceptable salt thereof. In someembodiments, the disease or condition is selected from the groupconsisting of hypertension, valvular heart diseases (such as aorticstenosis and Mitral valve regurgitation), metabolic syndromes (such asdiabetes and obesity), end stage renal disease, scleroderma, sleepapnea, amyloidosis, Fabry's disease, Friedreich Ataxia, Danon disease,Noonan syndrome, and Pompe disease.

Provided in other aspects are methods of treating a disease or conditionthat is associated with small left ventricular cavity and cavityobliteration, hyperdynamic left ventricular contraction, myocardialischemia, or cardiac fibrosis. Also provided are methods of treatingmuscular dystrophies (e.g., Duchenne muscular dystrophy) or glycogenstorage diseases.

Also provided are methods of inhibiting the cardiac sarcomere, whereinthe method involves contacting the cardiac sarcomere with a compound ofFormula (I) or any variation thereof, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition containing a compound ofFormula (I) or any variation thereof or a pharmaceutically acceptablesalt thereof.

DETAILED DESCRIPTION

Definitions

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

Throughout this application, unless the context indicates otherwise,references to a compound of Formula (I) includes all subgroups ofFormula (I) defined herein, such as Formula (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1),and (In-2), including all substructures, subgenera, preferences,embodiments, examples and particular compounds defined and/or describedherein. References to a compound of Formula (I) and subgroups thereof,such as Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii),(Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2), include ionicforms, polymorphs, pseudopolymorphs, amorphous forms, solvates,co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides,S-oxides), esters, prodrugs, isotopes and/or protected forms thereof. Insome embodiments, references to a compound of Formula (I) and subgroupsthereof, such as Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2), includepolymorphs, solvates, co-crystals, isomers, tautomers and/or oxidesthereof. In some embodiments, references to a compound of Formula (I)and subgroups thereof, such as Formula (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and(In-2), include polymorphs, solvates, and/or co-crystals thereof. Insome embodiments, references to a compound of Formula (I) and subgroupsthereof, such as Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2), includeisomers, tautomers and/or oxides thereof. In some embodiments,references to a compound of Formula (I) and subgroups thereof, such asFormula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2), include solvatesthereof.

“Alkyl” encompasses straight and branched carbon chains having theindicated number of carbon atoms, for example, from 1 to 20 carbonatoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, C₁₋₆alkyl encompasses both straight and branched chain alkyl of from 1 to 6carbon atoms. When an alkyl residue having a specific number of carbonsis named, all branched and straight chain versions having that number ofcarbons are intended to be encompassed; thus, for example, “propyl”includes n-propyl and isopropyl; and “butyl” includes n-butyl,sec-butyl, isobutyl and t-butyl. Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl,hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

When a range of values is given (e.g., C₁₋₆ alkyl), each value withinthe range as well as all intervening ranges are included. For example,“C₁₋₆ alkyl” includes C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₂₋₆, C₃₋₆, C₄₋₆,C₅₋₆, C₁₋₅, C₂₋₅, C₃₋₅, C₄₋₅, C₁₋₄, C₂₋₄, C₃₋₄, C₁₋₃, C₂₋₃, and C₁₋₂alkyl.

“Alkenyl” refers to an unsaturated branched or straight-chain alkylgroup having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to6 carbon atoms) and at least one carbon-carbon double bond. The groupmay be in either the cis or trans configuration (Z or E configuration)about the double bond(s). Alkenyl groups include, but are not limitedto, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g.,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl).

“Alkynyl” refers to an unsaturated branched or straight-chain alkylgroup having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to6 carbon atoms) and at least one carbon-carbon triple bond. Alkynylgroups include, but are not limited to, ethynyl, propynyl (e.g.,prop-1-yn-1-yl, prop-2-yn-1-yl) and butynyl (e.g., but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl).

“Cycloalkyl” indicates a non-aromatic, fully saturated carbocyclic ringhaving the indicated number of carbon atoms, for example, 3 to 10, or 3to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups may be monocyclicor polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well asbridged and caged ring groups (e.g., norbornane, bicyclo[2.2.2]octane).In addition, one ring of a polycyclic cycloalkyl group may be aromatic,provided the polycyclic cycloalkyl group is bound to the parentstructure via a non-aromatic carbon. For example, a1,2,3,4-tetrahydronaphthalen-1-yl group (wherein the moiety is bound tothe parent structure via a non-aromatic carbon atom) is a cycloalkylgroup, while 1,2,3,4-tetrahydronaphthalen-5-yl (wherein the moiety isbound to the parent structure via an aromatic carbon atom) is notconsidered a cycloalkyl group. Examples of polycyclic cycloalkyl groupsconsisting of a cycloalkyl group fused to an aromatic ring are describedbelow.

“Cycloalkenyl” indicates a non-aromatic carbocyclic ring, containing theindicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6ring carbon atoms) and at least one carbon-carbon double bond.Cycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic,tricyclic). Examples of cycloalkenyl groups include cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl, as wellas bridged and caged ring groups (e.g., bicyclo[2.2.2]octene). Inaddition, one ring of a polycyclic cycloalkenyl group may be aromatic,provided the polycyclic alkenyl group is bound to the parent structurevia a non-aromatic carbon atom. For example, inden-1-yl (wherein themoiety is bound to the parent structure via a non-aromatic carbon atom)is considered a cycloalkenyl group, while inden-4-yl (wherein the moietyis bound to the parent structure via an aromatic carbon atom) is notconsidered a cycloalkenyl group. Examples of polycyclic cycloalkenylgroups consisting of a cycloalkenyl group fused to an aromatic ring aredescribed below.

“Cycloalkynyl” refers to an unsaturated hydrocarbon group within acycloalkyl having at least one site of acetylenic unsaturation (i.e.,having at least one moiety of the formula CC). Cycloalkynyl can consistof one ring, such as cyclooctyne, or multiple rings. One cycloalkynylmoiety is an unsaturated cyclic hydrocarbon having from 5 to 10 annularcarbon atoms (a “C₅-C₁₀ cycloalkynyl”). Examples include cyclopentyne,cyclohexyne, cycloheptyne, cyclooctyne, cyclononyne, and the like.

“Aryl” indicates an aromatic carbocyclic ring having the indicatednumber of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms.Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).In some instances, both rings of a polycyclic aryl group are aromatic(e.g., naphthyl). In other instances, polycyclic aryl groups may includea non-aromatic ring fused to an aromatic ring, provided the polycyclicaryl group is bound to the parent structure via an atom in the aromaticring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (wherein themoiety is bound to the parent structure via an aromatic carbon atom) isconsidered an aryl group, while 1,2,3,4-tetrahydronaphthalen-1-yl(wherein the moiety is bound to the parent structure via a non-aromaticcarbon atom) is not considered an aryl group. Similarly, a1,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound tothe parent structure via an aromatic carbon atom) is considered an arylgroup, while 1,2,3,4-tetrahydroquinolin-1-yl group (wherein the moietyis bound to the parent structure via a non-aromatic nitrogen atom) isnot considered an aryl group. However, the term “aryl” does notencompass or overlap with “heteroaryl”, as defined herein, regardless ofthe point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl areheteroaryl groups). In some instances, aryl is phenyl or naphthyl. Incertain instances, aryl is phenyl. Additional examples of aryl groupscomprising an aromatic carbon ring fused to a non-aromatic ring aredescribed below.

“Heteroaryl” indicates an aromatic ring containing the indicated numberof atoms (e.g., 5 to 12, or 5 to 10 membered heteroaryl) made up of oneor more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, Oand S and with the remaining ring atoms being carbon. Heteroaryl groupsdo not contain adjacent S and O atoms. In some embodiments, the totalnumber of S and O atoms in the heteroaryl group is not more than 2. Insome embodiments, the total number of S and O atoms in the heteroarylgroup is not more than 1. Unless otherwise indicated, heteroaryl groupsmay be bound to the parent structure by a carbon or nitrogen atom, asvalency permits. For example, “pyridyl” includes 2-pyridyl, 3-pyridyland 4-pyridyl groups, and “pyrrolyl” includes 1-pyrrolyl, 2-pyrrolyl and3-pyrrolyl groups.

In some instances, a heteroaryl group is monocyclic. Examples includepyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole,1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole,oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole),thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine,pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine.

In some instances, both rings of a polycyclic heteroaryl group arearomatic. Examples include indole, isoindole, indazole, benzoimidazole,benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole,benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole,1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine,3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine,1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine,1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine,1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine,3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine,1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine,1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine,furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine,[1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine,oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine,[1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine,oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine,[1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine,oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine,[1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine,thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine,[1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine,thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine,[1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine,thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine,[1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine,thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine,[1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline,quinazoline, quinoxaline, phthalazine, naphthyridine (e.g.,1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine,1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine),imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole,1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole.

In other instances, polycyclic heteroaryl groups may include anon-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclicheteroaryl group is bound to the parent structure via an atom in thearomatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-ylgroup (wherein the moiety is bound to the parent structure via anaromatic carbon atom) is considered a heteroaryl group, while4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound tothe parent structure via a non-aromatic carbon atom) is not considered aheteroaryl group. Examples of polycyclic heteroaryl groups consisting ofa heteroaryl ring fused to a non-aromatic ring are described below.

“Heterocycloalkyl” indicates a non-aromatic, fully saturated ring havingthe indicated number of atoms (e.g., 3 to 10, or 3 to 7, memberedheterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4heteroatoms) selected from N, O and S and with the remaining ring atomsbeing carbon. Heterocycloalkyl groups may be monocyclic or polycyclic(e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups includeoxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl andthiomorpholinyl. Examples include thiomorpholine S-oxide andthiomorpholine S,S-dioxide. In addition, one ring of a polycyclicheterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl),provided the polycyclic heterocycloalkyl group is bound to the parentstructure via a non-aromatic carbon or nitrogen atom. For example, a1,2,3,4-tetrahydroquinolin-1-yl group (wherein the moiety is bound tothe parent structure via a non-aromatic nitrogen atom) is considered aheterocycloalkyl group, while 1,2,3,4-tetrahydroquinolin-8-yl group(wherein the moiety is bound to the parent structure via an aromaticcarbon atom) is not considered a heterocycloalkyl group. Examples ofpolycyclic heterocycloalkyl groups consisting of a heterocycloalkylgroup fused to an aromatic ring are described below.

“Heterocycloalkenyl” indicates a non-aromatic ring having the indicatednumber of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl)made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms)selected from N, O and S and with the remaining ring atoms being carbon,and at least one double bond derived by the removal of one molecule ofhydrogen from adjacent carbon atoms, adjacent nitrogen atoms, oradjacent carbon and nitrogen atoms of the correspondingheterocycloalkyl. Heterocycloalkenyl groups may be monocyclic orpolycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkenylgroups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl,2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl,2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl,2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g.,2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl,dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl),tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl,1,2,3,6-tetrahydropyridinyl) and dihydropyridine (e.g.,1,2-dihydropyridine, 1,4-dihydropyridine). In addition, one ring of apolycyclic heterocycloalkenyl group may be aromatic (e.g., aryl orheteroaryl), provided the polycyclic heterocycloalkenyl group is boundto the parent structure via a non-aromatic carbon or nitrogen atom. Forexample, a 1,2-dihydroquinolin-1-yl group (wherein the moiety is boundto the parent structure via a non-aromatic nitrogen atom) is considereda heterocycloalkenyl group, while 1,2-dihydroquinolin-8-yl group(wherein the moiety is bound to the parent structure via an aromaticcarbon atom) is not considered a heterocycloalkenyl group. Examples ofpolycyclic heterocycloalkenyl groups consisting of a heterocycloalkenylgroup fused to an aromatic ring are described below.

Examples of polycyclic rings consisting of an aromatic ring (e.g., arylor heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl,2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl,benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl,indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl,2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydrobenzofuranyl,1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl,2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl,2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl,1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl,2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl,4,5,6,7-tetrahydrobenzo[d]thiazolyl,5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl,4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one,indolin-3-one, isoindolin-1-one, 1,2-dihydroindazol-3-one,1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one,benzofuran-3(2H)-one, isobenzofuran-1(3H)-one,benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol-3(2H)-one,benzo[d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one,benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one,benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one,benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one,1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one,quinazolin-4(3H)-one, quinazoline-2,4(1H,3H)-dione,quinoxalin-2(1H)-one, quinoxaline-2,3(1H,4H)-dione, cinnolin-4(3H)-one,pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one,pyridazin-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one,1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one,1H-pyrrolo[2,3-b]pyridin-2(3H)-one,1,2-dihydropyrazolo[3,4-d]thiazol-3-one and4,5-dihydropyrrolo[3,4-d]thiazol-6-one. As discussed herein, whethereach ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl group is determined by the atomthrough which the moiety is bound to the parent structure.

The term “heterocycle,” “heterocyclyl,” or “heterocyclic” refers to asaturated, partially unsaturated, or unsaturated 4-12 membered ringcontaining at least one heteroatom independently selected from nitrogen,oxygen, and sulfur. Unless otherwise specified, the heteroatom may becarbon or nitrogen linked, a —CH₂— group can optionally be replaced by a—C(O)—, and a ring sulfur atom may be optionally oxidized to form asulfinyl or sulfonyl group. Heterocycles can be aromatic (heteroaryls)or non-aromatic. In addition, not all rings of a polycyclic heterocyclylgroup may be aromatic (e.g., aryl or heteroaryl). For example, a1,2,3,4-tetrahydroquinolin-1-yl group and a1,2,3,4-tetrahydroquinolin-8-yl group are both considered a heterocyclylgroup.

“Heterocycle,” “heterocyclyl,” or “heterocyclic” also includes bicyclic,tricyclic, and tetracyclic groups in which any of the above heterocyclicrings is fused to one or two rings independently selected from aryls,cycloalkyls, and heterocycles. Exemplary heterocycles include acridinyl,benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl,biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl,dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl,imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl,isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl,oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl,pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl,pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl,pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl,tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl,tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl,thiomorpholinyl, thiopyranyl, and triazolyl.

“Halogen” or “halo” refers to fluoro, chloro, bromo or iodo.

Unless otherwise indicated, compounds disclosed and/or described hereininclude all possible enantiomers, diastereomers, meso isomers and otherstereoisomeric forms, including racemic mixtures, optically pure formsand intermediate mixtures thereof. Enantiomers, diastereomers, mesoisomers and other stereoisomeric forms can be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques.Unless specified otherwise, when the compounds disclosed and/ordescribed herein contain olefinic double bonds or other centers ofgeometric asymmetry, it is intended that the compounds include both Eand Z isomers. When the compounds described herein contain moietiescapable of tautomerization, and unless specified otherwise, it isintended that the compounds include all possible tautomers.

“Protecting group” has the meaning conventionally associated with it inorganic synthesis, i.e., a group that selectively blocks one or morereactive sites in a multifunctional compound such that a chemicalreaction can be carried out selectively on another unprotected reactivesite, and such that the group can readily be removed after the selectivereaction is complete. A variety of protecting groups are disclosed, forexample, in T. H. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, New York (1999). Forexample, a “hydroxy protected form” contains at least one hydroxyl groupprotected with a hydroxyl protecting group. Likewise, amines and otherreactive groups may similarly be protected.

The term “pharmaceutically acceptable salt” refers to a salt of any ofthe compounds herein which are known to be non-toxic and are commonlyused in the pharmaceutical literature. In some embodiments, thepharmaceutically acceptable salt of a compound retains the biologicaleffectiveness of the compounds described herein and are not biologicallyor otherwise undesirable. Examples of pharmaceutically acceptable saltscan be found in Berge et al., Pharmaceutical Salts, J. PharmaceuticalSciences, January 1977, 66(1), 1-19. Pharmaceutically acceptable acidaddition salts can be formed with inorganic acids and organic acids.Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, andphosphoric acid. Organic acids from which salts can be derived include,for example, acetic acid, propionic acid, glycolic acid, pyruvic acid,lactic acid, oxalic acid, malic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid andsalicylic acid. Pharmaceutically acceptable base addition salts can beformed with inorganic and organic bases. Inorganic bases from whichsalts can be derived include, for example, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, andaluminum. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines; substituted aminesincluding naturally occurring substituted amines; cyclic amines; andbasic ion exchange resins. Examples of organic bases includeisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine. In some embodiments, thepharmaceutically acceptable base addition salt is selected fromammonium, potassium, sodium, calcium, and magnesium salts.

If the compound described herein is obtained as an acid addition salt,the free base can be obtained by basifying a solution of the acid salt.Conversely, if the compound is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds (see,e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences,January 1977, 66(1), 1-19). Those skilled in the art will recognizevarious synthetic methodologies that may be used to preparepharmaceutically acceptable addition salts.

A “solvate” is formed by the interaction of a solvent and a compound.Suitable solvents include, for example, water and alcohols (e.g.,ethanol). Solvates include hydrates having any ratio of compound towater, such as monohydrates, dihydrates and hemi-hydrates.

The term “substituted” means that the specified group or moiety bearsone or more substituents including, but not limited to, substituentssuch as alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy,acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo,hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl,heterocyclyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, andthe like. The term “unsubstituted” means that the specified group bearsno substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. When a group or moiety bearsmore than one substituent, it is understood that the substituents may bethe same or different from one another. In some embodiments, asubstituted group or moiety bears from one to five substituents. In someembodiments, a substituted group or moiety bears one substituent. Insome embodiments, a substituted group or moiety bears two substituents.In some embodiments, a substituted group or moiety bears threesubstituents. In some embodiments, a substituted group or moiety bearsfour substituents. In some embodiments, a substituted group or moietybears five substituents.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined herein. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible, and/or inherentlyunstable. It will also be understood that where a group or moiety isoptionally substituted, the disclosure includes both embodiments inwhich the group or moiety is substituted and embodiments in which thegroup or moiety is unsubstituted.

The compounds disclosed and/or described herein can be enriched isotopicforms, e.g., enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or ¹⁴C. Inone embodiment, the compound contains at least one deuterium atom. Suchdeuterated forms can be made, for example, by the procedure described inU.S. Pat. Nos. 5,846,514 and 6,334,997. Such deuterated compounds mayimprove the efficacy and increase the duration of action of compoundsdisclosed and/or described herein. Deuterium substituted compounds canbe synthesized using various methods, such as those described in: Dean,D., Recent Advances in the Synthesis and Applications of RadiolabeledCompounds for Drug Discovery and Development, Curr. Pharm. Des., 2000;6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds viaOrganometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; andEvans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem.,1981, 64(1-2), 9-32.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in pharmaceutical compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the pharmaceutical compositions.

The terms “patient,” “individual,” and “subject” refer to an animal,such as a mammal, bird, or fish. In some embodiments, the patient orsubject is a mammal. Mammals include, for example, mice, rats, dogs,cats, pigs, sheep, horses, cows and humans. In some embodiments, thepatient or subject is a human, for example a human that has been or willbe the object of treatment, observation or experiment. The compounds,compositions and methods described herein can be useful in both humantherapy and veterinary applications.

As used herein, the term “therapeutic” refers to the ability to modulatethe cardiac sarcomere. As used herein, “modulation” refers to a changein activity as a direct or indirect response to the presence of achemical entity as described herein, relative to the activity of in theabsence of the chemical entity. The change may be an increase inactivity or a decrease in activity, and may be due to the directinteraction of the chemical entity with the a target or due to theinteraction of the chemical entity with one or more other factors thatin turn affect the target's activity. For example, the presence of thechemical entity may, for example, increase or decrease the targetactivity by directly binding to the target, by causing (directly orindirectly) another factor to increase or decrease the target activity,or by (directly or indirectly) increasing or decreasing the amount oftarget present in the cell or organism.

The term “therapeutically effective amount” or “effective amount” refersto that amount of a compound disclosed and/or described herein that issufficient to affect treatment, as defined herein, when administered toa patient in need of such treatment. A therapeutically effective amountof a compound may be an amount sufficient to treat a disease responsiveto modulation of the cardiac sarcomere. The therapeutically effectiveamount will vary depending upon, for example, the subject and diseasecondition being treated, the weight and age of the subject, the severityof the disease condition, the particular compound, the dosing regimen tobe followed, timing of administration, the manner of administration, allof which can readily be determined by one of ordinary skill in the art.The therapeutically effective amount may be ascertained experimentally,for example by assaying blood concentration of the chemical entity, ortheoretically, by calculating bioavailability.

“Treatment” (and related terms, such as “treat”, “treated”, “treating”)includes one or more of: inhibiting a disease or disorder; slowing orarresting the development of clinical symptoms of a disease or disorder;and/or relieving a disease or disorder (i.e., causing relief from orregression of clinical symptoms). The term covers both complete andpartial reduction of the condition or disorder, and complete or partialreduction of clinical symptoms of a disease or disorder. Thus, compoundsdescribed and/or disclosed herein may prevent an existing disease ordisorder from worsening, assist in the management of the disease ordisorder, or reduce or eliminate the disease or disorder.

“ATPase” refers to an enzyme that hydrolyzes ATP. ATPases includeproteins comprising molecular motors such as the myosins.

As used herein, “selective binding” or “selectively binding” refers topreferential binding to a target protein in one type of muscle or musclefiber as opposed to other types. For example, a compound selectivelybinds to fast skeletal troponin C if the compound preferentially bindstroponin C in the troponin complex of a fast skeletal muscle fiber orsarcomere in comparison with troponin C in the troponin complex of aslow muscle fiber or sarcomere or with troponin C in the troponincomplex of a cardiac sarcomere.

It is understood that embodiments described herein as “comprising”include “consisting of” and “consisting essentially of” embodiments.

Compounds

Compounds and salts thereof (such as pharmaceutically acceptable salts)are detailed herein, including in the Brief Summary and in the appendedclaims. Also provided are the use of all of the compounds describedherein, including any and all stereoisomers, including geometric isomers(cis/trans), E/Z isomers, enantiomers, diastereomers, and mixturesthereof in any ratio including racemic mixtures, salts and solvates ofthe compounds described herein, as well as methods of making suchcompounds. Any compound described herein may also be referred to as adrug.

In one aspect, provided are compounds of Formula (I), orpharmaceutically acceptable salts thereof:

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedphenyl and substituted or unsubstituted pyridyl;

-   -   R^(2A), R^(2B), and R³ are defined by any one of (i)-(iii):    -   (i) R^(2A) is H or substituted or unsubstituted alkyl;        -   R^(2B) is selected from the group consisting of H,            substituted or unsubstituted alkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted cycloalkenyl, substituted or unsubstituted            cycloalkynyl, substituted or unsubstituted heterocyclyl,            substituted or unsubstituted aryl, and substituted or            unsubstituted heteroaryl; and        -   R³ is substituted or unsubstituted phenyl or substituted or            unsubstituted pyridyl;    -   or    -   (ii) R^(2A) is H or substituted or unsubstituted alkyl;        -   R^(2B) is substituted or unsubstituted phenyl or substituted            or unsubstituted pyridyl; and        -   R³ is substituted or unsubstituted alkyl;    -   or    -   (iii) R^(2A) and R^(2B) are taken together with the carbon atom        to which they are attached to form G¹, wherein G¹ is a        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted cycloalkenyl, substituted or unsubstituted        cycloalkynyl, or substituted or unsubstituted heterocyclyl ring,        each of which is optionally fused to a phenyl ring; and        -   R³ is selected from the group consisting of substituted or            unsubstituted alkyl, substituted or unsubstituted alkenyl,            substituted or unsubstituted alkynyl, substituted or            unsubstituted cycloalkyl, substituted or unsubstituted            cycloalkenyl, substituted or unsubstituted cycloalkynyl,            substituted or unsubstituted heterocyclyl, substituted or            unsubstituted aryl, and substituted or unsubstituted            heteroaryl;    -   R⁴ is H or substituted or unsubstituted alkyl; and    -   R⁵ is H or substituted or unsubstituted alkyl;        wherein, when one or more of provisions (a)-(c) apply, then R¹        is substituted or unsubstituted pyridyl or phenyl substituted        with at least one substituent other than methyl or methoxy:    -   (a) R^(2A) and R^(2B) are as defined by (i) and R³ is        substituted or unsubstituted phenyl;    -   (b) R^(2A) and R³ are as defined by (ii) and R^(2B) is        4-methoxyphenyl;    -   (c) R^(2A) and R^(2B) are as defined by (iii) and R³ is        4-methoxyphenylmethyl.

In some embodiments of Formula (I), R⁴ and R⁵ are each independently H.In some embodiments of Formula (I), at least one of R⁴ and R⁵ is otherthan H. In some embodiments of Formula (I), R⁴ is substituted orunsubstituted alkyl. In some embodiments of Formula (I), R⁴ is methyl.In some embodiments of Formula (I), R⁴ is alkyl substituted with alkoxy.In some embodiments of Formula (I), R⁴ is methoxymethyl. In someembodiments of Formula (I), R⁵ is substituted or unsubstituted alkyl. Insome embodiments of Formula (I), R⁵ is methyl. In some embodiments ofFormula (I), R⁵ is substituted alkyl. In some embodiments of Formula(I), R⁵ is hydroxymethyl.

In some embodiments of Formula (I), R¹ is unsubstituted pyridyl orunsubstituted phenyl. In some embodiments of Formula (I), R¹ is2-pyridyl. In some embodiments of Formula (I), R¹ is phenyl orpyridinyl, each of which is substituted with one or more (e.g., 1 or 2or 3 or 1-4 or 1-3 or 2-4) substituents independently selected from thegroup consisting of cyano, halo, substituted or unsubstituted alkoxy,substituted or unsubstituted alkyl, and substituted or unsubstituteddiazirinyl. In some embodiments of Formula (I), R¹ is pyridylsubstituted with one or two halo selected from the group consisting of Fand Cl. In some embodiments of Formula (I), R¹ is pyridyl substitutedwith —CF₃. In some embodiments of Formula (I), R¹ is phenyl substitutedwith one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo selectedfrom the group consisting of F and Cl. In some embodiments of Formula(I), R¹ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4or 1-3 or 2-4) methyl. In some embodiments of Formula (I), R¹ is phenylsubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)cyano. In some embodiments of Formula (I), R¹ is phenyl substituted withone or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) —CF₃. In someembodiments of Formula (I), R¹ is phenyl substituted with one halo andone cyano. In some embodiments of Formula (I), R¹ is phenyl substitutedwith one C₁ and one F. In some embodiments of Formula (I), R¹ is phenylsubstituted with one halo and one —CF₃. In some embodiments of Formula(I), R¹ is phenyl substituted with diazirinyl. In some embodiments ofFormula (I), R¹ is phenyl substituted with diazirinyl substituted withtrifluoromethyl.

In some embodiments of Formula (I), the carbon bearing the R^(2A) andR^(2B) moieties is in the “S” stereochemical configuration. In someembodiments of Formula (I), the carbon bearing the R^(2A) and R^(2B)moieties is in the “R” stereochemical configuration. It is understoodthat for any of the embodiments of formula (I) and subformulae thereofprovided herein, the disclosure includes embodiments wherein the carbonbearing the R^(2A) and R^(2B) moieties is in the “S” stereochemicalconfiguration and embodiments wherein the carbon bearing the R^(2A) andR^(2B) moieties is in the “R” stereochemical configuration.

It is understood that each of variables described herein may be combinedwith the other variables the same as if each and every combination werespecifically and individually listed. For example, each R¹ of Formula(I) may be combined with each of R^(2A), R^(2B), R³, R⁴, and R⁵ eitherindividually or collectively. It is also understood that this applies toFormula (I) and each of the subgroups: Formula (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1),and (In-2) described herein.

In another aspect, the compound of Formula (I) is a compound of Formula(Ia), or a pharmaceutically acceptable salt thereof:

wherein R¹ is selected from the group consisting of substituted orunsubstituted phenyl and substituted or unsubstituted pyridyl; R^(2A) isH or substituted or unsubstituted alkyl; R^(2B) is selected from thegroup consisting of H, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl; R³ is substituted orunsubstituted phenyl or substituted or unsubstituted pyridyl; R⁴ is H orsubstituted or unsubstituted alkyl; and R⁵ is H or substituted orunsubstituted alkyl; wherein, when R³ is substituted or unsubstitutedphenyl, R¹ is substituted or unsubstituted pyridyl or phenyl substitutedwith at least one substituent other than methyl or methoxy.

In some embodiments of Formula (Ia), R⁴ and R⁵ are each independently H.In some embodiments of Formula (Ia), at least one of R⁴ and R⁵ is otherthan H.

In some embodiments of Formula (Ia), R³ is substituted or unsubstitutedpyridyl. In some embodiments of Formula (Ia), R³ is 2-pyridyl. In someembodiments of Formula (Ia), R³ is unsubstituted phenyl. In someembodiments of Formula (Ia), R³ is phenyl or pyridyl, each of which issubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)halo substituents selected from the group consisting of F and Cl. Insome embodiments of Formula (Ia), R³ is phenyl or pyridyl, each of whichis substituted with two halo substituents selected from the groupconsisting of F and Cl. In some embodiments of Formula (Ia), R³ isphenyl or pyridyl, each of which is substituted with two F. In someembodiments of Formula (Ia), R³ is phenyl or pyridyl, each of which issubstituted with two Cl. In some embodiments of Formula (Ia), R³ isphenyl or pyridyl, each of which is substituted with one F and one Cl.In some embodiments of Formula (Ia), R³ is phenyl or pyridyl, each ofwhich is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3or 2-4) CN substituents. In some embodiments of Formula (Ia), R³ isphenyl or pyridyl, each of which is substituted with two CNsubstituents. In some embodiments of Formula (Ia), R³ is phenyl orpyridyl, each of which is substituted with one halo and one CNsubstituents. In some embodiments of Formula (Ia), R³ is phenyl orpyridyl, each of which is substituted with one Cl and one CN. In someembodiments of Formula (Ia), R³ is phenyl or pyridyl, each of which issubstituted with one F and one CN.

In some embodiments of Formula (Ia), R^(2A) is H. In some embodiments ofFormula (Ia), R^(2A) is substituted or unsubstituted alkyl. In someembodiments of Formula (Ia), R^(2A) is substituted or unsubstitutedmethyl. In some embodiments of Formula (Ia), R^(2A) is methyl.

In some embodiments of Formula (Ia), R^(2B) is H. In some embodiments ofFormula (Ia), R^(2B) is substituted or unsubstituted alkyl. In someembodiments of Formula (Ia), R^(2B) is selected from the groupconsisting of methyl, isopropyl, and propyl. In some embodiments ofFormula (Ia), R^(2B) is alkyl substituted with hydroxyl or substitutedor unsubstituted alkoxy. In some embodiments of Formula (Ia), R^(2B) ishydroxymethyl. In some embodiments of Formula (Ia), R^(2B) issubstituted alkoxyalkyl. In some embodiments of Formula (Ia), R^(2B) istrifluoromethoxymethyl. In some embodiments of Formula (Ia), R^(2B) issubstituted or unsubstituted cycloalkyl. In some embodiments of Formula(Ia), R^(2B) is substituted or unsubstituted C₃-C₇ cycloalkyl. In someembodiments of Formula (Ia), R^(2B) is cyclobutanyl. In some embodimentsof Formula (Ia), R^(2B) is substituted or unsubstituted heterocyclyl. Insome embodiments of Formula (Ia), R^(2B) is substituted or unsubstitutedC₃-C₇ heterocyclyl. In some embodiments of Formula (Ia), R^(2B) issubstituted or unsubstituted C₃-C₇ heterocyclyl, which contains one ormore (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) of N or O annular atoms.In some embodiments of Formula (Ia), R^(2B) is oxetanyl. In someembodiments of Formula (Ia), R^(2B) is 3-oxetanyl.

In some embodiments of Formula (Ia), R¹ is substituted or unsubstitutedpyridyl. In some embodiments of Formula (Ia), R¹ is 2-pyridyl. In someembodiments of Formula (Ia), R¹ is unsubstituted phenyl. In someembodiments of Formula (Ia), R¹ is phenyl or pyridyl, each of which issubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)substituents independently selected from the group consisting of cyano,halo, alkoxy, —CF₃, alkyl, and diazirinyl. In some embodiments ofFormula (Ia), R¹ is phenyl or pyridyl each of which is substituted withsubstituted alkyl. In some embodiments of Formula (Ia), R¹ is phenyl orpyridyl each of which is substituted with —CF₃. In some embodiments ofFormula (Ia), R¹ is phenyl substituted with 4-CF₃.

In some embodiments of Formula (Ia), R¹ is phenyl substituted with —CF₃and R³ is phenyl substituted with two halo substituents. In someembodiments of Formula (Ia), R¹ is phenyl substituted with —CF₃ and R³is phenyl substituted with one halo and one CN. In some embodiments ofFormula (Ia), R¹ is substituted or unsubstituted pyridyl and R³ isphenyl substituted with two halo. In some embodiments of Formula (Ia),R¹ is substituted or unsubstituted pyridyl and R³ is phenyl substitutedwith one halo and one CN. In some embodiments of Formula (Ia), R¹ is2-pyridyl and R³ is phenyl substituted with two halo. In someembodiments of Formula (Ia), R¹ is 2-pyridyl and R³ is phenylsubstituted with one halo and one CN. In some embodiments of Formula(Ia), R¹ is phenyl substituted with —CF₃ and R³ is phenyl.

In some embodiments of Formula (Ia), R¹ is phenyl substituted with —CF₃,R^(2A) is H, R^(2B) is 3-oxetanyl, R³ is phenyl substituted with one ormore substituents selected from the group consisting of F and Cl, R⁴ isH, and R⁵ is H. In some embodiments of Formula (Ia), R¹ is phenylsubstituted with —CF₃, R^(2A) is H, R^(2B) is 3-oxetanyl, R³ is pyridylsubstituted with one or more substituents selected from the groupconsisting of F and Cl, R⁴ is H, and R⁵ is H. In some embodiments ofFormula (Ia), R¹ is phenyl substituted with —CF₃, R^(2A) is H, R^(2B) isisopropyl, R³ is phenyl substituted with one or more substituentsselected from the group consisting of F and Cl, R⁴ is H, and R⁵ is H. Insome embodiments of Formula (Ia), R¹ is phenyl substituted with —CF₃,R^(2A) is H, R^(2B) is isopropyl, R³ is pyridyl substituted with one ormore substituents selected from the group consisting of F and Cl, R⁴ isH, and R⁵ is H.

In some embodiments of Formula (Ia): R⁴ and R⁵ are each independently H;R³ is phenyl or pyridyl, each of which is substituted with two halosubstituents selected from the group consisting of F and Cl; R^(2A) is Hor methyl; R^(2B) is selected from the group consisting of methyl,isopropyl, propyl, hydroxymethyl, trifluoromethoxymethyl, cyclobutanyl,and 3-oxetanyl; and R¹ is phenyl or pyridyl, each of which issubstituted with —CF₃.

In another aspect, the compound of Formula (I) is a compound of Formula(Ib), or a pharmaceutically acceptable salt thereof:

wherein R¹ is selected from the group consisting of substituted orunsubstituted phenyl and substituted or unsubstituted pyridyl; R^(2A) isH or substituted or unsubstituted alkyl; R^(2B) is substituted orunsubstituted phenyl or substituted or unsubstituted pyridyl; R³ issubstituted or unsubstituted alkyl; R⁴ is H or substituted orunsubstituted alkyl; and R⁵ is H or substituted or unsubstituted alkyl;wherein, when R^(2B) is 4-methoxyphenyl, R¹ is substituted orunsubstituted pyridyl or phenyl substituted with at least onesubstituent other than methyl or methoxy.

In some embodiments of Formula (Ib), R⁴ and R⁵ are each independently H.In some embodiments of Formula (Ib), at least one of R⁴ and R⁵ is otherthan H.

In some embodiments of Formula (Ib), R^(2A) is H. In some embodiments ofFormula (Ib), R^(2A) is substituted or unsubstituted alkyl. In someembodiments of Formula (Ib), R^(2A) is substituted or unsubstitutedmethyl. In some embodiments of Formula (Ia), R^(2A) is methyl.

In some embodiments of Formula (Ib), R^(2B) is substituted orunsubstituted pyridyl. In some embodiments of Formula (Ib), R^(2B) is2-pyridyl. In some embodiments, R^(2B) is substituted or unsubstitutedphenyl. In some embodiments of Formula (Ib), R^(2B) is phenyl orpyridyl, each of which is substituted with one or more (e.g., 1 or 2 or3 or 1-4 or 1-3 or 2-4) substituents independently selected from thegroup consisting of halo, substituted or unsubstituted alkoxy, andsubstituted or unsubstituted alkyl. In some embodiments of Formula (Ib),R^(2B) is pyridyl substituted with one or more substituents (e.g., 1 or2 or 3 or 1-4 or 1-3 or 2-4) selected from the group consisting of haloand substituted or unsubstituted alkyl. In some embodiments of Formula(Ib), R^(2B) is pyridyl substituted with one or more (e.g., 1 or 2 or 3or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ib), R^(2B)is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3or 2-4) halo. In some embodiments of Formula (Ib), R^(2B) is phenylsubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)—CF₃. In some embodiments of Formula (Ib), R^(2B) is phenyl substitutedwith one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) alkoxy. Insome embodiments of Formula (Ib), R^(2B) is phenyl substituted with oneor more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methoxy.

In some embodiments of Formula (Ib), R³ is substituted or unsubstitutedC₁-C₁₀ alkyl. In some embodiments of Formula (Ib), R³ is unsubstitutedC₁-C₁₀ alkyl. In some embodiments of Formula (Ib), R³ is unsubstitutedC₂-C₆ alkyl. In some embodiments of Formula (Ib), R³ is unsubstitutedC₃-C₅ alkyl. In some embodiments of Formula (Ib), R³ is unsubstituted C₃alkyl. In some embodiments of Formula (Ib), R³ is unsubstitutedisopropyl.

In some embodiments of Formula (Ib), R¹ is substituted or unsubstitutedpyridyl. In some embodiments of Formula (Ib), R¹ is 2-pyridyl. In someembodiments of Formula (Ib), R¹ is substituted or unsubstituted phenyl.In some embodiments of Formula (Ib), R¹ is phenyl or pyridinyl, each ofwhich is substituted with one or more substituents (e.g., 1 or 2 or 3 or1-4 or 1-3 or 2-4) independently selected from the group consisting ofcyano, halo, substituted or unsubstituted alkoxy, substituted orunsubstituted alkyl, and substituted or unsubstituted diazirinyl. Insome embodiments of Formula (Ib), R¹ is pyridyl substituted with one ormore (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodimentsof Formula (Ib), R¹ is pyridyl substituted with one or more (e.g., 1 or2 or 3 or 1-4 or 1-3 or 2-4) —CF₃. In some embodiments of Formula (Ib),R¹ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or1-3 or 2-4) halo. In some embodiments of Formula (Ib), R¹ is phenylsubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)—CF₃. In some embodiments of Formula (Ib), R¹ is phenyl substituted withone or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) —CN. In someembodiments of Formula (Ib), R¹ is phenyl substituted with one or more(e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methyl.

In some embodiments of Formula (Ib), R^(2B) is 4-methoxyphenyl and R¹ issubstituted or unsubstituted pyridyl. In some embodiments of Formula(Ib), R^(2B) is 4-methoxyphenyl and R¹ is 2-pyridyl. In some embodimentsof Formula (Ib), R^(2B) is 4-methoxyphenyl and R¹ is 2-pyridylsubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)halo. In some embodiments of Formula (Ib), R^(2B) is 4-methoxyphenyl andR¹ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or1-3 or 2-4) halo. In some embodiments of Formula (Ib), R^(2B) is4-methoxyphenyl and R¹ is phenyl substituted with 4-C₁.

In some embodiments of Formula (Ib), R¹ is pyridyl substituted with oneor more substituents independently selected from the group consisting ofhalo and —CF₃, R^(2A) is H, R^(2B) is pyridyl substituted with one ormore substituents selected from the group consisting of F and C₁, R³ isisopropyl, R⁴ is H, and R⁵ is H. In some embodiments of Formula (Ib), R¹is phenyl substituted with one or more substituents independentlyselected from the group consisting of halo, —CF₃, —CN, and methyl,R^(2A) is H, R^(2B) is pyridyl substituted with one or more substituentsselected from the group consisting of F and Cl, R³ is isopropyl, R⁴ isH, and R⁵ is H. In some embodiments of Formula (Ib), R¹ is pyridylsubstituted with one or more substituents independently selected fromthe group consisting of halo and —CF₃, R^(2A) is methyl, R^(2B) ispyridyl substituted with one or more substituents selected from thegroup consisting of F and Cl, R³ is isopropyl, R⁴ is H, and R⁵ is H. Insome embodiments of Formula (Ib), R¹ is phenyl substituted with one ormore substituents independently selected from the group consisting ofhalo, —CF₃, —CN, and methyl, R^(2A) is methyl, R^(2B) is pyridylsubstituted with one or more substituents selected from the groupconsisting of F and Cl, R³ is isopropyl, R⁴ is H, and R⁵ is H.

In another aspect, the compound of Formula (I) is a compound of Formula(Ic), or a pharmaceutically acceptable salt thereof:

wherein R¹ is selected from the group consisting of substituted orunsubstituted pyridyl and substituted or unsubstituted phenyl; R^(2A)and R^(2B) are taken together with the carbon atom to which they areattached to form G¹, wherein G¹ is a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl, substituted orunsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclylring, each of which is optionally fused to a phenyl ring; R³ is selectedfrom the group consisting of substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; R⁴ is H orsubstituted or unsubstituted alkyl; and R⁵ is H or substituted orunsubstituted alkyl; wherein, when R³ is 4-methoxyphenylmethyl, R¹ issubstituted or unsubstituted pyridyl or phenyl substituted with at leastone substituent other than methyl or methoxy.

In some embodiments of Formula (Ic), R⁴ and R⁵ are each independently H.In some embodiments of Formula (Ic), at least one of R⁴ and R⁵ is otherthan H. In some embodiments of Formula (Ic), R⁴ is substituted orunsubstituted alkyl. In some embodiments of Formula (Ic), R⁴ is methyl.In some embodiments of Formula (Ic), R⁴ is alkyl substituted withalkoxy. In some embodiments of Formula (Ic), R⁴ is methoxymethyl. Insome embodiments of Formula (Ic), R⁵ is substituted or unsubstitutedalkyl. In some embodiments of Formula (Ic), R⁵ is methyl. In someembodiments of Formula (Ic), R⁵ is substituted alkyl. In someembodiments of Formula (Ic), R⁵ is hydroxymethyl.

In some embodiments of Formula (Ic), G¹ is selected from the groupconsisting of substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, and substituted or unsubstituted2,3-dihydro-1H-indene. In some embodiments of Formula (Ic), G¹ issubstituted or unsubstituted C₃-C₆ cycloalkyl. In some embodiments ofFormula (Ic), G¹ is substituted or unsubstituted C₃-C₆ heterocyclyl. Insome embodiments of Formula (Ic), G¹ is substituted or unsubstitutedcyclopropyl. In some embodiments of Formula (Ic), G¹ is substituted orunsubstituted cyclobutanyl. In some embodiments of Formula (Ic), G¹ issubstituted or unsubstituted azetidinyl. In some embodiments of Formula(Ic), G¹ is substituted or unsubstituted tetrahydrofuranyl. In someembodiments of Formula (Ic), G¹ is substituted or unsubstitutedpyrrolidinyl. In some embodiments of Formula (Ic), G¹ is substituted orunsubstituted pyrrolidin-2-one-yl.

In some embodiments of Formula (Ic), G¹ is heterocyclyl or cycloalkyl,each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4or 1-3 or 2-4) substituents selected from the group consisting ofsubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted aminoacyl, substituted or unsubstituted acyl, substitutedor unsubstituted aminothionyl, substituted or unsubstitutedaminocarbonylamino, and substituted or unsubstituted alkyl. In someembodiments of Formula (Ic), G¹ is heterocyclyl substituted withsubstituted or unsubstituted phenyl. In some embodiments of Formula(Ic), G¹ is heterocyclyl substituted with phenyl which is substitutedwith halo. In some embodiments of Formula (Ic), G¹ is heterocyclylsubstituted with substituted or unsubstituted heteroaryl. In someembodiments of Formula (Ic), G¹ is heterocyclyl substituted withsubstituted or unsubstituted pyridyl. In some embodiments of Formula(Ic), G¹ is heterocyclyl substituted with pyridyl which is substitutedone or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituentsselected from the group consisting of alkyl, CN, hydroxyl,alkoxycarbonyl, methoxycarbonyl, alkoxy, carboxyl, cycloalkyl, halo, andaminoacyl. In some embodiments of Formula (Ic), G¹ is heterocyclylsubstituted with substituted or unsubstituted pyrimidyl. In someembodiments of Formula (Ic), G¹ is heterocyclyl substituted withsubstituted or unsubstituted pyrazolyl. In some embodiments of Formula(Ic), G¹ is heterocyclyl substituted with pyrazolyl which is substitutedwith alkyl. In some embodiments of Formula (Ic), G¹ is heterocyclylsubstituted with substituted or unsubstituted thiazolyl. In someembodiments of Formula (Ic), G¹ is heterocyclyl substituted thiazolylwhich is substituted with aminoacyl. In some embodiments of Formula(Ic), G¹ is heterocyclyl substituted with substituted or unsubstitutedalkoxycarbonyl. In some embodiments of Formula (Ic), G¹ is heterocyclylsubstituted with methoxycarbonyl. In some embodiments of Formula (Ic),G¹ is heterocyclyl substituted with substituted or unsubstitutedaminoacyl. In some embodiments of Formula (Ic), G¹ is heterocyclylsubstituted with methylaminoacyl. In some embodiments of Formula (Ic),G¹ is heterocyclyl substituted with aminoacyl which is substituted withone or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituentsselected from the group consisting of aryl, cycloalkyl, pyridyl,pyrazolyl, and alkoxyalkyl. In some embodiments of Formula (Ic), G¹ isheterocyclyl substituted with substituted or unsubstitutedpyridin-on-yl. In some embodiments of Formula (Ic), G¹ is heterocyclylsubstituted with pyridin-on-yl which is substituted with alkyl. In someembodiments of Formula (Ic), G¹ is heterocyclyl substituted withsubstituted or unsubstituted oxadiazolyl. In some embodiments of Formula(Ic), G¹ is heterocyclyl substituted with oxadiazolyl which issubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)substituents selected from the group consisting of alkyl and phenyl. Insome embodiments of Formula (Ic), G¹ is heterocyclyl substituted withsubstituted or unsubstituted 9-membered bicyclic heterocyclyl. In someembodiments of Formula (Ic), G¹ is heterocyclyl substituted with —C(O)H.In some embodiments of Formula (Ic), G¹ is heterocyclyl substituted withsubstituted or unsubstituted pyridazinyl. In some embodiments of Formula(Ic), G¹ is heterocyclyl substituted with pyridazinyl which issubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)substituents selected from the group consisting of halo, alkoxy, alkyl,and aminoacyl. In some embodiments of Formula (Ic), G¹ is heterocyclylsubstituted with substituted or unsubstituted aminothionyl. In someembodiments of Formula (Ic), G¹ is heterocyclyl substituted withaminothionyl which is substituted with alkyl. In some embodiments ofFormula (Ic), G¹ is heterocyclyl substituted with substituted orunsubstituted acyl. In some embodiments of Formula (Ic), G¹ isheterocyclyl substituted with acyl which is substituted with one or more(e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from thegroup consisting of cycloalkyl, alkyl, and heterocyclyl. In someembodiments of Formula (Ic), G¹ is heterocyclyl substituted with acylwhich is substituted with morpholinyl. In some embodiments of Formula(Ic), G¹ is heterocyclyl substituted with substituted or unsubstitutedaminocarbonylamino. In some embodiments of Formula (Ic), G¹ isheterocyclyl substituted with aminocarbonylamino which is substitutedwith one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituentsselected from the group consisting of cycloalkyl and heterocyclyl.

In some embodiments of Formula (Ic), G¹ is cycloalkyl substituted withsubstituted or unsubstituted phenyl. In some embodiments of Formula(Ic), G¹ is cycloalkyl substituted with substituted or unsubstitutedthiazolyl. In some embodiments of Formula (Ic), G¹ is cycloalkylsubstituted with thiazolyl which is substituted with alkyl. In someembodiments of Formula (Ic), G¹ is cycloalkyl substituted withsubstituted or unsubstituted oxazolyl. In some embodiments of Formula(Ic), G¹ is cycloalkyl substituted with oxazolyl which is substitutedwith alkyl. In some embodiments of Formula (Ic), G¹ is cycloalkylsubstituted with substituted or unsubstituted aminoacyl. In someembodiments of Formula (Ic), G¹ is cycloalkyl substituted with aminoacylwhich is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3or 2-4) substituents selected from the group consisting of alkyl,heterocyclyl, and cycloalkyl. In some embodiments of Formula (Ic), G¹ iscycloalkyl substituted with substituted or unsubstituted oxadizaolyl. Insome embodiments of Formula (Ic), G¹ is cycloalkyl substituted withoxadizaolyl which is substituted with one or more substituents (e.g., 1or 2 or 3 or 1-4 or 1-3 or 2-4) selected from the group consisting ofcycloalkyl and alkyl. In some embodiments of Formula (Ic), G¹ iscycloalkyl substituted with substituted or unsubstituted acyl. In someembodiments of Formula (Ic), G¹ is cycloalkyl substituted with acylwhich is substituted with heterocyclyl. In some embodiments of Formula(Ic), G¹ is cycloalkyl substituted with substituted or unsubstitutedaminocarbonylamino. In some embodiments of Formula (Ic), G¹ iscycloalkyl substituted with aminocarbonylamino which is substituted withone or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituentsselected from the group consisting of alkyl, cycloalkyl, andheterocyclyl. In some embodiments of Formula (Ic), G¹ is cycloalkylsubstituted with substituted or unsubstituted alkoxycarbonyl. In someembodiments of Formula (Ic), G¹ is cycloalkyl substituted withalkoxycarbonyl which is substituted with alkyl. In some embodiments ofFormula (Ic), G¹ is cycloalkyl substituted with substituted orunsubstituted alkyl. In some embodiments of Formula (Ic), G¹ iscycloalkyl substituted with alkyl which is substituted with hydroxyl. Insome embodiments of Formula (Ic), G¹ is cycloalkyl substituted withhydroxyl.

In some embodiments of Formula (Ic), R³ is selected from the groupconsisting of substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, andsubstituted or unsubstituted aryl. In some embodiments of Formula (Ic),R³ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or1-3 or 2-4) substituents selected from the group consisting of nitro,alkoxy, halo, cycloalkyl, cyano, alkenyl, alkoxycarbonyl,phenylcarbonyl, and alkyl. In some embodiments of Formula (Ic), R³ iscycloalkyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3or 2-4) substituents selected from the group consisting of alkyl, cyano,and halo. In some embodiments of Formula (Ic), R³ is alkyl substitutedwith one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituentsselected from the group consisting of alkoxy, cyano, and halo.

In some embodiments of Formula (Ic), R¹ is substituted or unsubstitutedpyridyl. In some embodiments of Formula (Ic), R¹ is 2-pyridyl. In someembodiments of Formula (Ic), R¹ is substituted or unsubstituted phenyl.In some embodiments of Formula (Ic), R¹ is phenyl or pyridinyl, each ofwhich is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3or 2-4) substituents independently selected from the group consisting ofcyano, halo, substituted or unsubstituted alkoxy, substituted orunsubstituted alkyl, and substituted or unsubstituted diazirinyl. Insome embodiments of Formula (Ic), R¹ is phenyl substituted with one ormore (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In some embodimentsof Formula (Ic), R¹ is phenyl substituted with one or more (e.g., 1 or 2or 3 or 1-4 or 1-3 or 2-4) —CF₃. In some embodiments of Formula (Ic), R¹is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3or 2-4) methyl. In some embodiments of Formula (Ic), R¹ is phenylsubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)diazirinyl. In some embodiments of Formula (Ic), R¹ is phenylsubstituted with trifluoromethyldiazirinyl.

In some embodiments of Formula (Ic), R¹ is phenyl substituted with Cland R³ is substituted with 4-methoxyphenylmethyl. In some embodiments ofFormula (Ic), R¹ is phenyl substituted with F and R³ is substituted with4-methoxyphenylmethyl. In some embodiments of Formula (Ic), R¹ is phenylsubstituted with —CF₃ and R³ is substituted with 4-methoxyphenylmethyl.In some embodiments of Formula (Ic), R¹ is phenyl substituted withtrifluoromethyldiazirinyl and R³ is substituted with4-methoxyphenylmethyl.

In another aspect, the compound of Formula (I) is a compound of Formula(Id), or a pharmaceutically acceptable salt thereof:

wherein R^(2A) is H or substituted or unsubstituted alkyl; R^(2B) isselected from the group consisting of H, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkynyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl; n is 0,1, or 2; each R^(1a) is independently selected from the group consistingof halo and cyano; and R⁴ is H.

In some embodiments of Formula (Id), R^(2A) is H. In some embodiments ofFormula (Id), R^(2A) is substituted or unsubstituted alkyl. In someembodiments of Formula (Id), R^(2A) is substituted or unsubstitutedmethyl. In some embodiments of Formula (Id), R^(2A) is methyl.

In some embodiments of Formula (Id), R^(2B) is H. In some embodiments ofFormula (Id), R^(2B) is substituted or unsubstituted alkyl. In someembodiments of Formula (Id), R^(2B) is selected from the groupconsisting of methyl, isopropyl, and propyl. In some embodiments ofFormula (Id), R^(2B) is alkyl substituted with hydroxyl or substitutedor unsubstituted alkoxy. In some embodiments of Formula (Id), R^(2B) ishydroxymethyl. In some embodiments of Formula (Id), R^(2B) issubstituted alkoxyalkyl. In some embodiments of Formula (Id), R^(2B) istrifluoromethoxymethyl. In some embodiments of Formula (Id), R^(2B) issubstituted or unsubstituted cycloalkyl. In some embodiments of Formula(Id), R^(2B) is substituted or unsubstituted C₃-C₇ cycloalkyl. In someembodiments of Formula (Id), R^(2B) is cyclobutanyl. In some embodimentsof Formula (Id), R^(2B) is substituted or unsubstituted heterocyclyl. Insome embodiments of Formula (Id), R^(2B) is substituted or unsubstitutedC₃-C₇ heterocyclyl. In some embodiments of Formula (Id), R^(2B) issubstituted or unsubstituted C₃-C₇ heterocyclyl, which contains one ormore (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) of S, N, or O atom. Insome embodiments of Formula (Id), R^(2B) is oxetanyl. In someembodiments of Formula (Id), R^(2B) is 3-oxetanyl.

In some embodiments of Formula (Id), n is 0. In some embodiments ofFormula (Id), n is 1. In some embodiments of Formula (Id), n is 2. Insome embodiments of Formula (Id), each R^(3a) is halo, such as C₁ or F.In some embodiments of Formula (Id), each R^(3a) is cyano. In someembodiments of Formula (Id), n is 2, one R^(3a) is halo and one R^(3a)is cyano. In some embodiments of Formula (Id), n is 2 and both R^(3a)are halo. In some embodiments of Formula (Id), n is 2 and both R^(3a)are cyano. In some embodiments of Formula (Id), n is 2 and R^(3a) are2-F and 4-F. In some embodiments of Formula (Id), n is 2 and R^(3a) are2-Cl and 4-Cl. In some embodiments of Formula (Id), n is 2 and R^(3a)are 2-F and 4-Cl. In some embodiments of Formula (Id), n is 2 and R^(3a)are 2-F and 4-CN. In some embodiments of Formula (Id), n is 2 and R^(3a)are 2-Cl and 4-CN. In some embodiments of Formula (Id), n is 2 andR^(3a) are 2-CN and 4-Cl. In some embodiments of Formula (Id), n is 2and R^(3a) are 2-CN and 4-F. In some embodiments of Formula (Id), n is 2and R^(3a) are 2-CN and 4-CN.

In some embodiments of Formula (Id), R^(2A) is H, R^(2B) istrifluoromethoxymethyl, n is 1, and R^(3a) is cyano or halo. In someembodiments of Formula (Id), R^(2A) is H, R^(2B) is 3-oxetanyl, n is 1,and R^(3a) is cyano or halo. In some embodiments of Formula (Id), R^(2A)is H, R^(2B) is cyclobutanyl, n is 1, and R^(3a) is cyano or halo. Insome embodiments of Formula (Id), R^(2A) is H, R^(2B) istrifluoromethoxymethyl, n is 2, and each R^(3a) is independently cyanoor halo. In some embodiments of Formula (Id), R^(2A) is H, R^(2B) is3-oxetanyl, n is 2, and each R^(3a) is independently cyano or halo. Insome embodiments of Formula (Id), R^(2A) is H, R^(2B) is cyclobutanyl, nis 2, and each R^(3a) is independently cyano or halo.

In another aspect, the compound of Formula (I) is a compound of Formula(Ie), or a pharmaceutically acceptable salt thereof:

wherein R¹ is selected from the group consisting of substituted orunsubstituted phenyl and substituted or unsubstituted pyridyl; R^(2A) isH or substituted or unsubstituted alkyl; R^(2B) is substituted orunsubstituted phenyl or substituted or unsubstituted pyridyl; and R⁴ isH; wherein, when R^(2B) is 4-methoxyphenyl, R¹ is substituted orunsubstituted pyridyl or phenyl substituted with at least onesubstituent other than methyl or methoxy.

In some embodiments of Formula (Ie), R^(2A) is H. In some embodiments ofFormula (Ie), R^(2A) is substituted or unsubstituted alkyl. In someembodiments of Formula (Ie), R^(2A) is substituted or unsubstitutedmethyl. In some embodiments of Formula (Ie), R^(2A) is methyl.

In some embodiments of Formula (Ie), R^(2B) is substituted orunsubstituted pyridyl. In some embodiments of Formula (Ie), R^(2B) is2-pyridyl. In some embodiments, R^(2B) is substituted or unsubstitutedphenyl. In some embodiments of Formula (Ie), R^(2B) is phenyl orpyridyl, each of which is substituted with one or more (e.g., 1 or 2 or3 or 1-4 or 1-3 or 2-4) substituents independently selected from thegroup consisting of halo, substituted or unsubstituted alkoxy, andsubstituted or unsubstituted alkyl. In some embodiments of Formula (Ie),R²Bis pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or1-3 or 2-4) substituents selected from the group consisting of halo andsubstituted or unsubstituted alkyl. In some embodiments of Formula (Ie),R^(2B) is pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4or 1-3 or 2-4) halo. In some embodiments of Formula (Ie), R^(2B) isphenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or2-4) halo. In some embodiments of Formula (Ie), R^(2B) is phenylsubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)—CF₃. In some embodiments of Formula (Ie), R^(2B) is phenyl substitutedwith one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) alkoxy. Insome embodiments of Formula (Ie), R²Bis phenyl substituted with one ormore (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methoxy.

In some embodiments of Formula (Ie), R¹ is substituted or unsubstitutedpyridyl. In some embodiments of Formula (Ie), R¹ is 2-pyridyl. In someembodiments of Formula (Ie), R¹ is unsubstituted phenyl. In someembodiments of Formula (Ie), R¹ is phenyl or pyridinyl, each of which issubstituted with one or more substituents independently selected fromthe group consisting of cyano, halo, and substituted or unsubstitutedalkyl. In some embodiments of Formula (Ie), R¹ is pyridyl substitutedwith one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halo. In someembodiments of Formula (Ie), R¹ is pyridyl substituted with one or more(e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) —CF₃. In some embodiments ofFormula (Ie), R¹ is phenyl substituted with one or more (e.g., 1 or 2 or3 or 1-4 or 1-3 or 2-4) halo. In some embodiments of Formula (Ie), R¹ isphenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or2-4) —CF₃. In some embodiments of Formula (Ie), R¹ is phenyl substitutedwith one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) CN. In someembodiments of Formula (Ie), R¹ is phenyl substituted with one or more(e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methyl.

In some embodiments of Formula (Ie), R^(2B) is 4-methoxyphenyl and R¹ issubstituted or unsubstituted pyridyl. In some embodiments of Formula(Ie), R^(2B) is 4-methoxyphenyl and R¹ is 2-pyridyl. In some embodimentsof Formula (Ie), R^(2B) is 4-methoxyphenyl and R¹ is 2-pyridylsubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)halo. In some embodiments of Formula (Ie), R^(2B) is 4-methoxyphenyl andR¹ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or1-3 or 2-4) halo. In some embodiments of Formula (Ie), R^(2B) is4-methoxyphenyl and R¹ is phenyl substituted with 4-C₁.

In another aspect, the compound of Formula (I) is a compound of Formula(If), or a pharmaceutically acceptable salt thereof:

wherein G¹ is selected from the group consisting of substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkynyl, and substituted orunsubstituted heterocyclyl ring, each of which is optionally fused to aphenyl ring; R^(1a) is selected from the group consisting of cyano,halo, substituted or unsubstituted alkoxy, substituted or unsubstitutedalkyl, and substituted or unsubstituted heterocyclyl; each R^(2a) isindependently selected from the group consisting of substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl,substituted or unsubstituted acyl, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted aminocarbonylamino, andsubstituted or unsubstituted alkyl; n is 0, 1, 2, or 3; R³ is selectedfrom the group consisting of substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, and substituted or unsubstituted aryl; and R⁴ is H;wherein, when R³ is 4-methoxyphenylmethyl, R^(1a) is not methyl ormethoxy.

It is understood that the G¹ group is the ring including the carbon atomthat it shares with the piperazinedione ring.

In some embodiments of Formula (If), G¹ is selected from the groupconsisting of substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, and substituted or unsubstituted2,3-dihydro-1H-indene. In some embodiments of Formula (Ic), G¹ issubstituted or unsubstituted C₃-C₆ cycloalkyl. In some embodiments ofFormula (Ic), G¹ is substituted or unsubstituted C₃-C₆ heterocyclyl. Insome embodiments of Formula (Ic), G¹ is substituted or unsubstitutedcyclopropyl. In some embodiments of Formula (Ic), G¹ is substituted orunsubstituted cyclobutanyl. In some embodiments of Formula (Ic), G¹ issubstituted or unsubstituted azetidinyl. In some embodiments of Formula(Ic), G¹ is substituted or unsubstituted tetrahydrofuranyl. In someembodiments of Formula (Ic), G¹ is substituted or unsubstitutedpyrrolidinyl. In some embodiments of Formula (Ic), G¹ is substituted orunsubstituted pyrrolidin-2-one-yl.

In some embodiments of Formula (If), G¹ is heterocyclyl substituted withone or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) R^(2a). Each R^(2a)selected from the group consisting of substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted orunsubstituted acyl, substituted or unsubstituted aminothionyl,substituted or unsubstituted aminocarbonylamino, and substituted orunsubstituted alkyl. In some embodiments of Formula (If), R^(2a) issubstituted or unsubstituted phenyl. In some embodiments of Formula(If), R^(2a) is phenyl substituted with halo. In some embodiments ofFormula (If), R^(2a) is substituted or unsubstituted heteroaryl. In someembodiments of Formula (If), R^(2a) is substituted or unsubstitutedpyridyl. In some embodiments of Formula (If), R^(2a) is pyridylsubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)substituents selected from the group consisting of alkyl, CN, hydroxyl,alkoxycarbonyl, methoxycarbonyl, alkoxy, carboxyl, cycloalkyl, halo, andaminoacyl. In some embodiments of Formula (If), R^(2a) is substituted orunsubstituted pyrimidyl. In some embodiments of Formula (If), R^(2a) issubstituted or unsubstituted pyrazolyl. In some embodiments of Formula(If), R^(2a) is pyrazolyl substituted with alkyl. In some embodiments ofFormula (If), R^(2a) is substituted or unsubstituted thiazolyl. In someembodiments of Formula (If), R^(2a) is thiazolyl substituted withaminoacyl. In some embodiments of Formula (If), R^(2a) is substituted orunsubstituted alkoxycarbonyl. In some embodiments of Formula (If),R^(2a) is methoxycarbonyl. In some embodiments of Formula (If), R^(2a)is substituted or unsubstituted aminoacyl. In some embodiments ofFormula (If), R^(2a) is methylaminoacyl. In some embodiments of Formula(If), R^(2a) is aminoacyl substituted with one or more (e.g., 1 or 2 or3 or 1-4 or 1-3 or 2-4) substituents selected from the group consistingof aryl, cycloalkyl, pyridyl, pyrazolyl, and alkoxyalkyl. In someembodiments of Formula (If), R^(2a) is substituted or unsubstitutedpyridin-one-yl. In some embodiments of Formula (If), R^(2a) ispyridin-on-yl substituted with alkyl. In some embodiments of Formula(If), R^(2a) is substituted or unsubstituted oxadiazolyl. In someembodiments of Formula (If), R^(2a) is oxadiazolyl substituted with oneor more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selectedfrom the group consisting of alkyl and phenyl. In some embodiments ofFormula (If), R^(2a) is substituted or unsubstituted 9-membered bicyclicheterocyclyl. In some embodiments of Formula (If), R^(2a) is —C(O)H. Insome embodiments of Formula (If), R^(2a) is substituted or unsubstitutedpyridazinyl. In some embodiments of Formula (If), R^(2a) is pyridazinylsubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)substituents selected from the group consisting of halo, alkoxy, alkyl,and aminoacyl. In some embodiments of Formula (If), R^(2a) issubstituted or unsubstituted aminothionyl. In some embodiments ofFormula (If), R^(2a) is aminothionyl substituted with alkyl. In someembodiments of Formula (If), R^(2a) is substituted or unsubstitutedacyl. In some embodiments of Formula (If), R^(2a) is acyl substitutedwith one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituentsselected from the group consisting of cycloalkyl, alkyl, andheterocyclyl. In some embodiments of Formula (If), R^(2a) is acylsubstituted with morpholinyl. In some embodiments of Formula (If),R^(2a) is substituted or unsubstituted aminocarbonylamino. In someembodiments of Formula (If), R^(2a) is aminocarbonylamino substitutedwith one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituentsselected from the group consisting of cycloalkyl and heterocyclyl.

In some embodiments of Formula (If), G¹ is cycloalkyl substituted withone or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) R^(2a). In someembodiments of Formula (If), R^(2a) is substituted or unsubstitutedphenyl. In some embodiments of Formula (If), R^(2a) is substituted orunsubstituted thiazolyl. In some embodiments of Formula (If), R^(2a) isthiazolyl substituted with alkyl. In some embodiments of Formula (If),R^(2a) is substituted or unsubstituted oxazolyl. In some embodiments ofFormula (If), R^(2a) is oxazolyl substituted with alkyl. In someembodiments of Formula (If), R^(2a) is substituted or unsubstitutedaminoacyl. In some embodiments of Formula (If), R^(2a) is aminoacylsubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)substituents selected from the group consisting of alkyl, heterocyclyl,and cycloalkyl. In some embodiments of Formula (If), R^(2a) issubstituted or unsubstituted oxadiazolyl. In some embodiments of Formula(If), R^(2a) is oxadiazolyl substituted with one or more (e.g., 1 or 2or 3 or 1-4 or 1-3 or 2-4) substituents selected from the groupconsisting of cycloalkyl and alkyl. In some embodiments of Formula (If),R^(2a) is substituted or unsubstituted acyl. In some embodiments ofFormula (If), R^(2a) is acyl substituted with heterocyclyl. In someembodiments of Formula (If), R^(2a) is substituted or unsubstitutedaminocarbonylamino. In some embodiments of Formula (If), R^(2a) isaminocarbonylamino substituted with one or more (e.g., 1 or 2 or 3 or1-4 or 1-3 or 2-4) substituents selected from the group consisting ofalkyl, cycloalkyl, and heterocyclyl. In some embodiments of Formula(If), R^(2a) is substituted or unsubstituted alkoxycarbonyl. In someembodiments of Formula (If), R^(2a) is alkoxycarbonyl substituted withalkyl. In some embodiments of Formula (If), R^(2a) is substituted orunsubstituted alkyl. In some embodiments of Formula (If), R^(2a) isalkyl substituted with hydroxyl. In some embodiments of Formula (If),R^(2a) is hydroxyl.

In some embodiments of Formula (If), R³ is selected from the groupconsisting of substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, andsubstituted or unsubstituted aryl. In some embodiments of Formula (If),R³ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or1-3 or 2-4) substituents selected from the group consisting of nitro,alkoxy, halo, cycloalkyl, cyano, alkenyl, alkoxycarbonyl,phenylcarbonyl, and alkyl. In some embodiments of Formula (If), R³ iscycloalkyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3or 2-4) substituents selected from the group consisting of alkyl, cyano,and halo. In some embodiments of Formula (If), R³ is alkyl substitutedwith one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituentsselected from the group consisting of alkoxy, cyano, and halo.

In some embodiments of Formula (If), R^(1a) is selected from the groupconsisting of cyano, halo, substituted or unsubstituted alkoxy,substituted or unsubstituted alkyl, and substituted or unsubstituteddiazirinyl. In some embodiments of Formula (If), R^(1a) is halo. In someembodiments of Formula (If), R^(1a) is —CF₃. In some embodiments ofFormula (If), R^(1a) is methyl. In some embodiments of Formula (If),R^(1a) is diazirinyl. In some embodiments of Formula (If), R^(1a) istrifluoromethyldiazirinyl.

In some embodiments of Formula (If), R^(1a) is Cl and R³ is substitutedwith 4-methoxyphenylmethyl. In some embodiments of Formula (If), R^(1a)is F and R³ is substituted with 4-methoxyphenylmethyl. In someembodiments of Formula (If), R^(1a) is —CF₃ and R³ is substituted with4-methoxyphenylmethyl. In some embodiments of Formula (If), R^(1a) istrifluoromethyldiazirinyl and R³ is substituted with4-methoxyphenylmethyl.

In some embodiments of Formula (I), Formula (Ic), and Formula (If), G¹is selected from the group consisting of:

wherein * indicates the point of attachment to the parent structure,

R^(2a). is selected from the group consisting of substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl,substituted or unsubstituted acyl, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted aminocarbonylamino, andsubstituted or unsubstituted alkyl; and

n is 0, 1, 2, or 3.

In some embodiments of Formula (I), Formula (Ic), and Formula (If), G¹is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)R^(2a) independently selected from the group consisting of:

wherein n is 0-3 and each X is independently selected from the groupconsisting of H, halo, alkyl, cyano, hydroxyl, cycloalkyl,alkoxycarbonyl, carboxyl, aminoacyl, aryl, heteroaryl, alkoxy,alkoxyalkyl, aminothionyl, and heterocyclyl.

In another aspect, provided is a compound of Formula (Ig), or apharmaceutically acceptable salt thereof:

wherein R^(1a) is selected from the group consisting of cyano, halo,substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl,and substituted or unsubstituted heterocyclyl; R^(2a) is selected fromthe group consisting of substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted orunsubstituted acyl, substituted or unsubstituted aminosulfonyl,substituted or unsubstituted aminocarbonylamino, and substituted orunsubstituted alkyl; n is 0, 1, 2, or 3; each R^(3a) is independentlyselected from the group consisting of substituted or unsubstitutedalkoxy, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, halo, nitro, and cyano; and R⁴ is H.

In some embodiments of Formula (Ig), R^(1a) is selected from the groupconsisting of cyano, halo, substituted or unsubstituted alkoxy,substituted or unsubstituted alkyl, and substituted or unsubstituteddiazirinyl. In some embodiments of Formula (Ig), R^(1a) is halo. In someembodiments of Formula (Ig), R^(1a) is —CF₃. In some embodiments ofFormula (Ig), R^(1a) is methyl. In some embodiments of Formula (Ig),R^(1a) is diazirinyl. In some embodiments of Formula (Ig), R^(1a) istrifluoromethyldiazirinyl.

In some embodiments of Formula (Ig), n is 0. In some embodiments ofFormula (Ig), n is 1. In some embodiments of Formula (Ig), n is 2. Insome embodiments of Formula (Ig), each R^(3a) is halo, such as C₁ or F.In some embodiments of Formula (Ig), each R^(3a) is cyano. In someembodiments of Formula (Ig), n is 2, one R^(3a) is halo and one R^(3a)is cyano. In some embodiments of Formula (If), n is 2 and both R^(3a)are halo. In some embodiments of Formula (If), n is 2 and both R^(3a)are cyano. In some embodiments of Formula (If), n is 2 and R^(3a) are2-F and 4-F. In some embodiments of Formula (Ig), n is 2 and R^(3a) are2-Cl and 4-Cl. In some embodiments of Formula (Ig), n is 2 and R^(3a)are 2-F and 4-Cl. In some embodiments of Formula (Ig), n is 2 and R^(3a)are 3-F and 4-Cl. In some embodiments of Formula (Ig), n is 2 and R^(3a)are 3-F and 4-CN. In some embodiments of Formula (Ig), n is 2 and R^(3a)are 4-F and 3-Cl. In some embodiments of Formula (Ig), n is 2 and R^(3a)are 2-F and 4-CN. In some embodiments of Formula (Ig), n is 2 and R^(3a)are 2-Cl and 4-CN. In some embodiments of Formula (Ig), n is 2 andR^(3a) are 2-CN and 4-Cl. In some embodiments of Formula (Ig), n is 2and R^(3a) are 2-CN and 4-F. In some embodiments of Formula (Ig), n is 2and R^(3a) are 2-CN and 4-CN. In some embodiments of Formula (Ig),R^(3a) is nitro. In some embodiments of Formula (Ig), n is 1 and R^(3a)is 4-nitro. In some embodiments of Formula (Ig), n is 1 and R^(3a) is4-Cl or 3-Cl. In some embodiments of Formula (Ig), n is 1 and R^(3a) is4-F or 3-F. In some embodiments of Formula (Ig), n is 1 and R^(1a) is4-CN or 3-CN. In some embodiments of Formula (Ig), R^(1a) isdifluoromethoxy. In some embodiments of Formula (Ig), R^(1a) ispropenyl. In some embodiments of Formula (Ig), R^(3a) is methyl. In someembodiments of Formula (Ig), n is 2 and R^(3a) are 3-methyl and 4-Cl. Insome embodiments of Formula (Ig), n is 2 and R^(3a) are 3-methyl and4-CN. In some embodiments of Formula (Ig), n is 2 and R^(3a) are 3-F and4-difluoromethoxy.

In some embodiments of Formula (Ig), R^(2a) is substituted orunsubstituted phenyl. In some embodiments of Formula (Ig), R^(2a) issubstituted or unsubstituted aminoacyl. In some embodiments of Formula(Ig), R^(2a) is aminoacyl substituted with one or more (e.g., 1 or 2 or3 or 1-4 or 1-3 or 2-4) substituents selected from the group consistingof alkyl, heterocyclyl, and cycloalkyl. In some embodiments of Formula(Ig), R^(2a) is substituted or unsubstituted oxadiazolyl. In someembodiments of Formula (Ig), R^(2a) is oxadiazolyl substituted with oneor more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selectedfrom the group consisting of cycloalkyl and alkyl. In some embodimentsof Formula (Ig), R^(2a) is substituted or unsubstituted acyl. In someembodiments of Formula (Ig), R^(2a) is acyl substituted withheterocyclyl. In some embodiments of Formula (Ig), R^(2a) is acylsubstituted with aryl. In some embodiments of Formula (Ig), R^(2a) isacyl substituted with phenyl. In some embodiments of Formula (Ig),R^(2a) is acyl substituted with alkyl. In some embodiments of Formula(Ig), R^(2a) is substituted or unsubstituted pyridyl. In someembodiments of Formula (Ig), R^(2a) is pyridyl substituted with CN orhalo. In some embodiments of Formula (Ig), R^(2a) is substituted orunsubstituted aminocarbonylamino. In some embodiments of Formula (Ig),R^(2a) is aminocarbonylamino substituted with one or more (e.g., 1 or 2or 3 or 1-4 or 1-3 or 2-4) substituents selected from the groupconsisting of alkyl, cycloalkyl, and heterocyclyl. In some embodimentsof Formula (Ig), R^(2a) is substituted or unsubstituted alkoxycarbonyl.In some embodiments of Formula (Ig), R^(2a) is alkoxycarbonylsubstituted with alkyl. In some embodiments of Formula (Ig), R^(2a) issubstituted or unsubstituted alkyl. In some embodiments of Formula (Ig),R^(2a) is alkyl substituted with hydroxyl. In some embodiments ofFormula (Ig), R^(2a) is alkyl substituted with halo. In some embodimentsof Formula (Ig), R^(2a) is hydroxyl. In some embodiments of Formula(Ig), R^(2a) is substituted or unsubstituted aminosulfonyl. In someembodiments of Formula (Ig), R^(2a) is aminosulfonyl substituted withalkyl.

In another aspect, provided is a compound of Formula (Ih), or apharmaceutically acceptable salt thereof:

wherein R^(1a) is selected from the group consisting of cyano, halo,substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl,and substituted or unsubstituted heterocyclyl; R^(2a) is selected fromthe group consisting of substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted orunsubstituted acyl, substituted or unsubstituted aminosulfonyl,substituted or unsubstituted aminocarbonylamino, and substituted orunsubstituted alkyl; R³ is selected from the group consisting ofsubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, and substitutedor unsubstituted aryl; and R⁴ is H; wherein, when R³ is4-methoxyphenylmethyl, R^(1a) is not methyl or methoxy.

In some embodiments of Formula (Ih), R^(1a) is selected from the groupconsisting of cyano, halo, substituted or unsubstituted alkoxy,substituted or unsubstituted alkyl, and substituted or unsubstituteddiazirinyl. In some embodiments of Formula (Ih), R^(1a) is halo. In someembodiments of Formula (Ih), R^(1a) is —CF₃. In some embodiments ofFormula (Ih), R^(1a) is methyl. In some embodiments of Formula (Ih),R^(1a) is diazirinyl. In some embodiments of Formula (Ih), R^(1a) istrifluoromethyldiazirinyl.

In some embodiments of Formula (Ih), R^(2a) is substituted orunsubstituted phenyl. In some embodiments of Formula (Ih), R^(2a) issubstituted or unsubstituted aminoacyl. In some embodiments of Formula(Ih), R^(2a) is aminoacyl substituted with one or more (e.g., 1 or 2 or3 or 1-4 or 1-3 or 2-4) substituents selected from the group consistingof alkyl, heterocyclyl, and cycloalkyl. In some embodiments of Formula(Ih), R^(2a) is substituted or unsubstituted oxadiazolyl. In someembodiments of Formula (Ih), R^(2a) is oxadiazolyl substituted with oneor more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selectedfrom the group consisting of cycloalkyl and alkyl. In some embodimentsof Formula (Ih), R^(2a) is substituted or unsubstituted acyl. In someembodiments of Formula (Ih), R^(2a) is acyl substituted withheterocyclyl. In some embodiments of Formula (Ih), R^(2a) is acylsubstituted with aryl. In some embodiments of Formula (Ih), R^(2a) isacyl substituted with phenyl. In some embodiments of Formula (Ih),R^(2a) is acyl substituted with alkyl. In some embodiments of Formula(Ih), R^(2a) is substituted or unsubstituted pyridyl. In someembodiments of Formula (Ih), R^(2a) is pyridyl substituted with CN orhalo. In some embodiments of Formula (Ih), R^(2a) is substituted orunsubstituted aminocarbonylamino. In some embodiments of Formula (Ih),R^(2a) is aminocarbonylamino substituted with one or more (e.g., 1 or 2or 3 or 1-4 or 1-3 or 2-4) substituents selected from the groupconsisting of alkyl, cycloalkyl, and heterocyclyl. In some embodimentsof Formula (Ih), R^(2a) is substituted or unsubstituted alkoxycarbonyl.In some embodiments of Formula (Ih), R^(2a) is alkoxycarbonylsubstituted with alkyl. In some embodiments of Formula (Ih), R^(2a) issubstituted or unsubstituted alkyl. In some embodiments of Formula (Ih),R^(2a) is alkyl substituted with hydroxyl. In some embodiments ofFormula (Ih), R^(2a) is alkyl substituted with halo. In some embodimentsof Formula (Ih), R^(2a) is hydroxyl. In some embodiments of Formula(Ih), R^(2a) is substituted or unsubstituted aminosulfonyl. In someembodiments of Formula (Ih), R^(2a) is aminosulfonyl substituted withalkyl. In some embodiments of Formula (Ih), R^(2a) is substituted orunsubstituted thiazolyl. In some embodiments of Formula (Ih), R^(2a) isthiazolyl substituted with alkyl. In some embodiments of Formula (Ih),R^(2a) is substituted or unsubstituted oxazolyl. In some embodiments ofFormula (Ih), R^(2a) is oxazolyl substituted with alkyl.

In some embodiments of Formula (Ih), R³ is selected from the groupconsisting of substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, andsubstituted or unsubstituted aryl. In some embodiments of Formula (Ih),R³ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or1-3 or 2-4) substituents selected from the group consisting of nitro,alkoxy, halo, cycloalkyl, cyano, alkenyl, alkoxycarbonyl,phenylcarbonyl, and alkyl. In some embodiments, R³ is phenyl substitutedwith CN and F. In some embodiments of Formula (Ih), R³ is alkylsubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)substituents selected from the group consisting of alkoxy, cyano, andhalo. In some embodiments, R³ is isopropyl.

In another aspect, provided is a compound of Formula (Ii), or apharmaceutically acceptable salt thereof:

wherein R^(1a) is selected from the group consisting of cyano, halo,substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl,and substituted or unsubstituted heterocyclyl; R^(2a) is selected fromthe group consisting of substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted orunsubstituted acyl, substituted or unsubstituted aminosulfonyl,substituted or unsubstituted aminocarbonylamino, and substituted orunsubstituted alkyl; R³ is selected from the group consisting ofsubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, and substitutedor unsubstituted aryl; R⁴ is H; R⁵ is H or substituted or unsubstitutedalkyl; and X and Y are independently —CH₂— or —C(O)—; wherein, when R³is 4-methoxyphenylmethyl, R^(1a) is not methyl or methoxy.

In some embodiments of Formula (Ii), R^(1a) is selected from the groupconsisting of cyano, halo, substituted or unsubstituted alkoxy,substituted or unsubstituted alkyl, and substituted or unsubstituteddiazirinyl. In some embodiments of Formula (Ii), R^(1a) is halo. In someembodiments of Formula (Ii), R^(1a) is —CF₃. In some embodiments ofFormula (Ii), R^(1a) is methyl. In some embodiments of Formula (Ii),R^(1a) is Cl. In some embodiments of Formula (Ih), R^(1a) istrifluoromethyldiazirinyl.

In some embodiments of Formula (Ii), R^(2a) is substituted orunsubstituted phenyl. In some embodiments of Formula (Ii), R^(2a) issubstituted or unsubstituted pyridyl. In some embodiments of Formula(Ii), R^(2a) is pyridyl substituted with alkyl, CN or halo. In someembodiments of Formula (Ii), R^(2a) is substituted or unsubstitutedpyrimidyl. In some embodiments of Formula (Ii), R^(2a) is substituted orunsubstituted pyridazinyl. In some embodiments of Formula (Ii), R^(2a)is pyridazinyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or1-3 or 2-4) substituents selected from the group consisting of halo,alkoxy, alkyl, and aminoacyl. In some embodiments of Formula (Ii),R^(2a) is substituted or unsubstituted aminoacyl. In some embodiments ofFormula (Ii), R^(2a) is aminoacyl substituted with one or more (e.g., 1or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the groupconsisting of alkyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl. Insome embodiments of Formula (Ii), R^(2a) is substituted or unsubstitutedpyrazolyl. In some embodiments of Formula (Ii), R^(2a) is pyrazolylsubstituted with alkyl. In some embodiments of Formula (Ii), R^(2a) issubstituted or unsubstituted oxadiazolyl. In some embodiments of Formula(Ii), R^(2a) is oxadiazolyl substituted with one or more (e.g., 1 or 2or 3 or 1-4 or 1-3 or 2-4) substituents selected from the groupconsisting of cycloalkyl and alkyl. In some embodiments of Formula (Ii),R^(2a) is substituted or unsubstituted acyl. In some embodiments ofFormula (Ii), R^(2a) is acyl substituted with heterocyclyl. In someembodiments of Formula (Ii), R^(2a) is acyl substituted with aryl. Insome embodiments of Formula (Ii), R^(2a) is acyl substituted withphenyl. In some embodiments of Formula (Ii), R^(2a) is acyl substitutedwith alkyl. In some embodiments of Formula (Ii), R^(2a) is substitutedor unsubstituted aminocarbonylamino. In some embodiments of Formula(Ii), R^(2a) is aminocarbonylamino substituted with one or more (e.g., 1or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the groupconsisting of alkyl, cycloalkyl, and heterocyclyl. In some embodimentsof Formula (Ii), R^(2a) is substituted or unsubstituted alkoxycarbonyl.In some embodiments of Formula (Ii), R^(2a) is alkoxycarbonylsubstituted with alkyl. In some embodiments of Formula (Ii), R^(2a) issubstituted or unsubstituted alkyl. In some embodiments of Formula (Ii),R^(2a) is alkyl substituted with hydroxyl. In some embodiments ofFormula (Ii), R^(2a) is alkyl substituted with halo. In some embodimentsof Formula (Ii), R^(2a) is hydroxyl. In some embodiments of Formula(Ii), R^(2a) is substituted or unsubstituted aminosulfonyl. In someembodiments of Formula (Ii), R^(2a) is aminosulfonyl substituted withalkyl. In some embodiments of Formula (Ii), R^(2a) is substituted orunsubstituted thiazolyl. In some embodiments of Formula (Ii), R^(2a) isthiazolyl substituted with alkyl. In some embodiments of Formula (Ii),R^(2a) is substituted or unsubstituted oxazolyl. In some embodiments ofFormula (Ii), R^(2a) is oxazolyl substituted with alkyl.

In some embodiments of Formula (Ii), R³ is selected from the groupconsisting of substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, andsubstituted or unsubstituted aryl. In some embodiments of Formula (Ii),R³ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or1-3 or 2-4) substituents selected from the group consisting of nitro,alkoxy, halo, cycloalkyl, cyano, alkenyl, alkoxycarbonyl,phenylcarbonyl, and alkyl. In some embodiments of Formula (Ii), R³ isphenyl substituted with CN and F. In some embodiments of Formula (Ii),R³ is phenyl substituted with CN or Cl. In some embodiments of Formula(Ii), R³ is cycloalkyl substituted with one or more (e.g., 1 or 2 or 3or 1-4 or 1-3 or 2-4) substituents selected from the group consisting ofalkyl, cyano, and halo. In some embodiments of Formula (Ii), R³ iscyclopropyl substituted with alkyl. In some embodiments of Formula (Ii),R³ is alkyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or1-3 or 2-4) substituents selected from the group consisting of alkoxy,cyano, and halo. In some embodiments of Formula (Ii), R³ is isopropyl,methyl, or ethyl. In some embodiments of Formula (Ii), R³ is substitutedor unsubstituted heterocyclyl. In some embodiments of Formula (Ii), R³is furanyl.

In some embodiments of Formula (Ii), R⁵ is substituted or unsubstitutedalkyl. In some embodiments of Formula (Ii), R⁵ is methyl. In someembodiments of Formula (Ii), R⁵ is substituted alkyl. In someembodiments of Formula (Ii), R⁵ is hydroxymethyl. In some embodiments ofFormula (Ii), R⁵ is H.

In some embodiments of Formula (Ii), X and Y are independently —CH₂— or—C(O)—. In some embodiments of Formula (Ii), X and Y are both —CH₂—. Insome embodiments of Formula (Ii), X is —CH₂— and Y is —C(O)—. In someembodiments of Formula (Ii), Y is —CH₂— and X is —C(O)—.

In another aspect, the compound of Formula (I) is a compound of Formula(Ij), or a pharmaceutically acceptable salt thereof:

wherein R¹ is substituted or unsubstituted phenyl; each R^(2b) isindependently substituted or unsubstituted alkyl; R³ is substituted orunsubstituted phenyl or substituted or unsubstituted pyridyl; R⁴ is H;R⁵ is H or substituted or unsubstituted alkyl; n is 0, 1, or 2; and q is0 or 1; wherein, when R³ is substituted or unsubstituted phenyl, then R¹is substituted or unsubstituted pyridyl or phenyl substituted with atleast one substituent other than methyl or methoxy.

In some embodiments of Formula (Ij), R¹ is substituted or unsubstitutedphenyl. In some embodiments of Formula (Ij), R¹ is phenyl substitutedwith one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituentsselected from the group consisting of halo, unsubstituted alkyl, andalkyl substituted with one or more halo groups. In some embodiments ofFormula (Ij), R¹ is phenyl substituted with halo. In some embodiments ofFormula (Ij), R¹ is phenyl substituted with F or C₁. In some embodimentsof Formula (Ij), R¹ is phenyl substituted with unsubstituted alkyl. Insome embodiments of Formula (Ij), R¹ is phenyl substituted with methylor ethyl. In some embodiments of Formula (Ij), R¹ is phenyl substitutedwith alkyl substituted with one or more halo groups. In some embodimentsof Formula (Ij), R¹ is phenyl substituted with —CHF₂ or —CF₃. In someembodiments of Formula (Ij), R¹ is phenyl substituted with 4-Cl. In someembodiments of Formula (Ij), R¹ is phenyl substituted with 4-CF₃. Insome embodiments of Formula (Ij), R¹ is phenyl substituted with two ormore groups selected from the group consisting of F, Cl, methyl and—CF₃. In some embodiments of Formula (Ij), R¹ is phenyl substituted withtwo F groups. In some embodiments of Formula (Ij), R¹ is phenylsubstituted with F and Cl. In some embodiments of Formula (Ij), R¹ isphenyl substituted with F and methyl. In some embodiments of Formula(Ij), R¹ is phenyl substituted with F and —CF₃.

In some embodiments of Formula (Ij), n is 0, 1, or 2. In someembodiments of Formula (Ij), n is 0. In some embodiments of Formula(Ij), n is 1. In some embodiments of Formula (Ij), n is 1, and R^(2b) issubstituted or unsubstituted alkyl. In some embodiments of Formula (Ij),n is 1, and R^(2b) is unsubstituted alkyl. In some embodiments ofFormula (Ij), n is 1, and R^(2b) is methyl.

In some embodiments of Formula (Ij), R³ is substituted or unsubstitutedphenyl. In some embodiments of Formula (Ij), R³ is phenyl substitutedwith one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituentsselected from the group consisting of halo and cyano. In someembodiments of Formula (Ij), R³ is phenyl substituted with halo. In someembodiments of Formula (Ij), R³ is phenyl substituted with F, Cl, or Br.In some embodiments of Formula (Ij), R³ is phenyl substituted withcyano. In some embodiments of Formula (Ij), R³ is phenyl substitutedwith two or more groups selected from the group consisting of F, Cl, Br,and cyano. In some embodiments of Formula (Ij), R³ is phenyl substitutedwith F and Cl. In some embodiments of Formula (Ij), R³ is phenylsubstituted with F and Br. In some embodiments of embodiments of Formula(Ij), R³ is phenyl substituted with F and cyano.

In some embodiments of Formula (Ij), R³ is substituted or unsubstitutedpyridinyl. In some embodiments of Formula (Ij), R³ is pyridinylsubstituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4)substituents selected from the group consisting of halo, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, andsubstituted or unsubstituted alkoxy. In some embodiments of Formula(Ij), R³ is pyridinyl substituted with halo. In some embodiments ofFormula (Ij), R³ is pyridinyl substituted with F or Cl. In someembodiments of Formula (Ij), R³ is pyridinyl substituted withunsubstituted alkyl. In some embodiments of Formula (Ij), R³ ispyridinyl substituted with methyl. In some embodiments of Formula (Ij),R³ is pyridinyl substituted with unsubstituted alkenyl. In someembodiments of Formula (Ij), R³ is pyridinyl substituted with —CH═CH₂.In some embodiments of Formula (Ij), R³ is pyridinyl substituted withalkoxy optionally substituted with halo. In some embodiments of Formula(Ij), R³ is pyridinyl substituted with methoxy or —OCHF₂. In someembodiments of Formula (Ij), R³ is pyridinyl substituted with two ormore groups selected from the group consisting of halo, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, andsubstituted or unsubstituted alkoxy. In some embodiments of Formula(Ij), R³ is pyridinyl substituted with F and Cl. In some embodiments ofFormula (Ij), R³ is pyridinyl substituted with Cl and methyl. In someembodiments of Formula (Ij), R³ is pyridinyl substituted with F andmethoxy. In some embodiments of Formula (Ij), R³ is pyridinylsubstituted with F and —OCHF₂. In some embodiments of Formula (Ij), R³is pyridinyl substituted with F and —CH═CH₂. In some embodiments ofFormula (Ij), R³ is substituted or unsubstituted pyridin-2-yl.

In some embodiments of Formula (Ij), R⁵ is H. In some embodiments ofFormula (Ij), R⁵ is substituted or unsubstituted alkyl. In someembodiments of Formula (Ij), R⁵ is methyl.

In some embodiments of Formula (Ij), q is 0. In some embodiments ofFormula (Ij), q is 1.

In some embodiments of Formula (Ij), R¹ is phenyl substituted with oneor more substituents selected from the group consisting of F, Cl,methyl, —CHF₂, and —CF₃, n is 0, R³ is pyridinyl substituted with one ormore substituents selected from the group consisting of F, Cl, methyl,—CH═CH₂, methoxy, and —OCHF₂, R⁵ is H, and q is 0. In some embodimentsof Formula (Ij), R¹ is phenyl substituted with one or more substituentsselected from the group consisting of F, Cl, methyl, —CHF₂, and —CF₃, nis 0, R³ is phenyl substituted with one or more substituents selectedfrom the group consisting of F, Cl, Br, and cyano, R⁵ is H, and q is 0.In some embodiments of Formula (Ij), R¹ is phenyl substituted with oneor more substituents selected from the group consisting of F, Cl,methyl, —CHF₂, and —CF₃, n is 1, R^(2b) is methyl, R³ is pyridinylsubstituted with one or more substituents selected from the groupconsisting of F, Cl, methyl, —CH═CH₂, methoxy, and —OCHF₂, R⁵ is H, andq is 0. In some embodiments of Formula (Ij), R¹ is phenyl substitutedwith one or more substituents selected from the group consisting of F,Cl, methyl, —CHF₂, and —CF₃, n is 1, R^(2b) is methyl, R³ is phenylsubstituted with one or more substituents selected from the groupconsisting of F, Cl, Br, and cyano, R⁵ is H, and q is 0. In someembodiments of Formula (Ij), R¹ is phenyl substituted with one or moresubstituents selected from the group consisting of F, Cl, methyl, —CHF₂,and —CF₃, n is 0, R³ is pyridinyl substituted with one or moresubstituents selected from the group consisting of F, Cl, methyl,—CH═CH₂, methoxy, and —OCHF₂, R⁵ is H, and q is 1. In some embodimentsof Formula (Ij), R¹ is phenyl substituted with one or more substituentsselected from the group consisting of F, Cl, methyl, —CHF₂, and —CF₃, nis 0, R³ is phenyl substituted with one or more substituents selectedfrom the group consisting of F, Cl, Br, and cyano, R⁵ is H, and q is 1.In some embodiments of Formula (Ij), R¹ is phenyl substituted with oneor more substituents selected from the group consisting of F, Cl,methyl, —CHF₂, and —CF₃, n is 1, R^(2b) is methyl, R³ is pyridinylsubstituted with one or more substituents selected from the groupconsisting of F, Cl, methyl, —CH═CH₂, methoxy, and —OCHF₂, R⁵ is H, andq is 1. In some embodiments of Formula (Ij), R¹ is phenyl substitutedwith one or more substituents selected from the group consisting of F,Cl, methyl, —CHF₂, and —CF₃, n is 1, R^(2b) is methyl, R³ is phenylsubstituted with one or more substituents selected from the groupconsisting of F, C₁, Br, and cyano, R⁵ is H, and q is 1.

In some embodiments of Formula (Ij): R¹ is phenyl substituted with onesubstituent selected from the group consisting of F, Cl, methyl, ethyl,—CHF₂ or —CF₃; n is 0 or n is 1, and R^(2b) is methyl; R³ is pyridinylsubstituted with two substituents selected from the group consisting ofF, Cl, methyl, —CH═CH₂, methoxy, and —OCHF₂; R⁵ is H; and q is 0 or 1.

In another aspect, the compound of Formula (I) is a compound of Formula(Ik-1), or a pharmaceutically acceptable salt thereof:

wherein R^(2A) is H or substituted or unsubstituted alkyl; R^(2B) isselected from the group consisting of substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, and substituted orunsubstituted heterocyclyl; m is 0, 1, or 2; p is 0, 1, or 2; eachR^(1a) is independently selected from the group consisting of halo andsubstituted or unsubstituted alkyl; each R^(1a) is independentlyselected from the group consisting of halo, cyano, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, andsubstituted or unsubstituted alkoxy; and R⁴ is H.

In some embodiments of Formula (Ik-1), R^(2A) is H. In some embodimentsof Formula (Ik-1), R^(2A) is substituted or unsubstituted alkyl. In someembodiments of Formula (Ik-1), R^(2A) is substituted or unsubstitutedmethyl. In some embodiments of Formula (Ik-1), R^(2A) is methyl.

In some embodiments of Formula (Ik-1), R^(2B) is substituted orunsubstituted alkyl. In some embodiments of Formula (Ik-1), R^(2B) isisopropyl. In some embodiments of Formula (Ik-1), R^(2B) is substitutedalkyl. In some embodiments of Formula (Ik-1), R^(2B) is alkylsubstituted with halo. In some embodiments of Formula (Ik-1), R^(2B) is—CHF₂. In some embodiments of Formula (Ik-1), R^(2B) is alkylsubstituted with —OH. In some embodiments of Formula (Ik-1), R^(2B) is—CH(OH)CH₃. In some embodiments of Formula (Ik-1), R^(2B) is —CH₂OH. Insome embodiments of Formula (Ik-1), R^(2B) is —CH₂CH₂SCH₃. In someembodiments of Formula (Ik-1), R^(2B) is —CH₂CH₂S(O)₂CH₃. In someembodiments of Formula (Ik-1), R^(2B) is —CH₂N(H)C(O)CH₃. In someembodiments of Formula (Ik-1), R^(2B) is —CH₂CH₂C(O)NH₂. In someembodiments of Formula (Ik-1), R^(2B) is alkyl substituted withheterocyclyl. In some embodiments of Formula (Ik-1), R^(2B) is C₁-C₂alkyl substituted with heterocyclyl. In some embodiments of Formula(Ik-1), R^(2B) is methyl substituted with oxetanyl. In some embodimentsof Formula (Ik-1), R^(2B) is methyl substituted with azetidinyl.

In some embodiments of Formula (Ik-1), R^(2B) is substituted orunsubstituted cycloalkyl. In some embodiments of Formula (Ik-1), R^(2B)is substituted or unsubstituted C₃-C₅ cycloalkyl. In some embodiments ofFormula (Ik-1), R^(2B) is unsubstituted cyclopropyl. In some embodimentsof Formula (Ik-1), R^(2B) is unsubstituted cyclobutyl. In someembodiments of Formula (Ik-1), R^(2B) is cyclobutyl substituted withhydroxyl. In some embodiments of Formula (Ik-1), R^(2B) is cyclobutylsubstituted with methoxy. In some embodiments of Formula (Ik-1), R^(2B)is polycyclic cycloalkyl. In some embodiments of Formula (Ik-1), R^(2B)is substituted or unsubstituted bicyclo[1.1.1]pentanyl. In someembodiments of Formula (Ik-1), R^(2B) is bicyclo[1.1.1]pentanylsubstituted by a group selected from the group consisting of hydroxy,alkoxycarbonyl, carbamoyl, and hydroxymethyl.

In some embodiments of Formula (Ik-1), R^(2B) is substituted orunsubstituted heterocyclyl. In some embodiments of Formula (Ik-1),R^(2B) is substituted or unsubstituted 4-membered to 7-memberedheterocyclyl. In some embodiments of Formula (Ik-1), R^(2B) issubstituted or unsubstituted 4-membered to 7-membered heterocyclyl,which contains one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) ofN, O, or S atom. In some embodiments of Formula (Ik-1), R^(2B) issubstituted or unsubstituted 4- to 6-membered heterocyclyl containingone N atom. In some embodiments of Formula (Ik-1), R^(2B) is substitutedor unsubstituted azetidinyl. In some embodiments of Formula (Ik-1),R^(2B) is 3-azetidinyl substituted with aminoacyl or acyl. In someembodiments of Formula (Ik-1), R^(2B) is substituted or unsubstituted 4-to 6-membered heterocyclyl containing one O atom. In some embodiments ofFormula (Ik-1), R^(2B) is substituted or unsubstituted oxetanyl. In someembodiments of Formula (Ik-1), R^(2B) is unsubstituted 3-oxetanyl. Insome embodiments of Formula (Ik-1), R^(2B) is 3-oxetanyl substitutedwith methyl. In some embodiments of Formula (Ik-1), R^(2B) issubstituted or unsubstituted tetrahydro-2H-pyranyl. In some embodimentsof Formula (Ik-1), R^(2B) is unsubstituted tetrahydro-2H-pyranyl. Insome embodiments of Formula (Ik-1), R^(2B) is substituted orunsubstituted 4- to 6-membered heterocyclyl containing one S atom. Insome embodiments of Formula (Ik-1), R^(2B) is substituted orunsubstituted 4-tetrahydro-2H-thiopyranyl.

In some embodiments of Formula (Ik-1), both R^(2A) and R^(2B) aremethyl. In some embodiments of Formula (Ik-1), R^(2A) is methyl andR^(2B) is substituted methyl. In some embodiments of Formula (Ik-1),R^(2A) is methyl and R^(2B) is —CH₂OH. In some embodiments of Formula(Ik-1), R^(2A) is methyl and R^(2B) is —CH₂N(H)C(O)CH₃. In someembodiments of Formula (Ik-1), R^(2A) is methyl and R^(2B) is —CHF₂.

In some embodiments of Formula (Ik-1), m is 0. In some embodiments ofFormula (Ik-1), m is 1. In some embodiments of Formula (Ik-1), m is 2.In some embodiments of Formula (Ik-1), each R^(1a) is independentlyselected from the group consisting of halo and substituted orunsubstituted alkyl. In some embodiments of Formula (Ik-1), m is 1, andR^(1a) is on the 4-position of the phenyl moiety. In some embodiments ofFormula (Ik-1), m is 1, and R^(1a) is halo. In some embodiments ofFormula (Ik-1), m is 1, and R^(1a) is 4-F. In some embodiments ofFormula (Ik-1), m is 1, and R^(1a) is 4-Cl. In some embodiments ofFormula (Ik-1), m is 1, and R^(1a) is substituted or unsubstituted C₁-C₃alkyl. In some embodiments of Formula (Ik-1), m is 1, and R^(1a) is4-methyl. In some embodiments of Formula (Ik-1), m is 1, and R^(1a) is4-ethyl. In some embodiments of Formula (Ik-1), m is 1, and R^(1a) is4-CHF₂. In some embodiments of Formula (Ik-1), m is 1, and R^(1a) is4-CF₃. In some embodiments of Formula (Ik-1), m is 2, and the two R^(1a)groups are on the 3-position and 4-position of the phenyl moiety. Insome embodiments of Formula (Ik-1), m is 2, and R^(1a) are 3-F and 4-F.In some embodiments of Formula (Ik-1), m is 2, and R^(1a) are 3-F and4-Cl. In some embodiments of Formula (Ik-1), m is 2, and R^(1a) are 3-Fand 4-methyl. In some embodiments of Formula (Ik-1), m is 2, and R^(1a)are 3-F and 4-CF₃. In some embodiments of Formula (Ik-1), m is 2, andR^(1a) are 3-Cl and 4-F. In some embodiments of Formula (Ik-1), m is 2,and R^(1a) are 3-methyl and 4-F.

In some embodiments of Formula (Ik-1), p is 0. In some embodiments ofFormula (Ik-1), p is 1. In some embodiments of Formula (Ik-1), p is 2.In some embodiments of Formula (Ik-1), p is 2, and each R^(3a) isindependently selected from the group consisting of halo, cyano,substituted or unsubstituted C₁-C₃ alkyl, substituted or unsubstitutedC₂-C₃ alkenyl, and substituted or unsubstituted C₁-C₃ alkoxy. In someembodiments of Formula (Ik-1), p is 2, and each R^(3a) is independentlyF, Cl, Br, cyano, methyl, —CH═CH₂, —OCH₃, or —OCHF₂. In some embodimentsof Formula (Ik-1), p is 2, and at least one R^(3a) is F. In someembodiments of Formula (Ik-1), p is 2, and at least one R^(3a) is 3-F.In some embodiments of Formula (Ik-1), p is 2, and one R^(3a) is 3-F andone R^(3a) is on the 5-position of the pyridinyl moiety and is selectedfrom the group consisting of halo, cyano, unsubstituted C₁-C₃ alkyl,unsubstituted C₂-C₃ alkenyl, and substituted or unsubstituted C₁-C₃alkoxy. In some embodiments of Formula (Ik-1), p is 2, and R^(3a) are3-F and 5-Cl. In some embodiments of Formula (Ik-1), p is 2, and R^(3a)are 3-F and 5-Br. In some embodiments of Formula (Ik-1), p is 2, andR^(3a) are 3-F and 5-cyano. In some embodiments of Formula (Ik-1), p is2, and R^(3a) are 3-F and 5-methyl. In some embodiments of Formula(Ik-1), p is 2, and R^(3a) are 3-F and 5-ethenyl. In some embodiments ofFormula (Ik-1), p is 2, and R^(3a) are 3-F and 5-methoxy. In someembodiments of Formula (Ik-1), p is 2, and R^(3a) are 3-F and 5-OCH₃. Insome embodiments of Formula (Ik-1), p is 2, and R^(3a) are 3-F and5-OCHF₂. In some embodiments of Formula (Ik-1), p is 2, and R^(3a) are3-methyl and 5-C₁.

In some embodiments of Formula (Ik-1), R^(2A) is H, R^(2B) is isopropyl,m is 1, R^(1a) is selected from the group consisting of F, Cl, and —CF₃,p is 1, and R^(3a) is selected from the group consisting of F, Cl, andcyano. In some embodiments of Formula (Ik-1), R^(2A) is H, R^(2B) is3-oxetanyl, m is 1, R^(1a) is selected from the group consisting of F,Cl, and —CF₃, p is 1, and R^(3a) is selected from the group consistingof F, Cl, and cyano. In some embodiments of Formula (Ik-1), R^(2A) ismethyl, R^(2B) is methyl, m is 1, R^(1a) is selected from the groupconsisting of F, Cl, and —CF₃, p is 1, and R^(3a) is selected from thegroup consisting of F, Cl, and cyano.

In some embodiments of Formula (Ik-1), R^(2A) is H, R^(2B) is isopropyl,m is 1, R^(1a) is selected from the group consisting of F, Cl, and —CF₃,p is 2, and each R^(3a) is independently selected from the groupconsisting of F, Cl, and cyano. In some embodiments of Formula (Ik-1),R^(2A) is H, R^(2B) is 3-oxetanyl, m is 1, R^(1a) is selected from thegroup consisting of F, Cl, and —CF₃, p is 2, and each R^(3a) isindependently selected from the group consisting of F, Cl, and cyano. Insome embodiments of Formula (Ik-1), R^(2A) is methyl, R^(2B) is methyl,m is 1, R^(1a) is selected from the group consisting of F, Cl, and —CF₃,p is 2, and each R^(3a) is independently selected from the groupconsisting of F, Cl, and cyano.

In some embodiments of Formula (Ik-1), R^(2A) is H, R^(2B) is isopropyl,m is 2, each R^(1a) is independently selected from the group consistingof F, Cl, and —CF₃, p is 1, and R^(3a) is selected from the groupconsisting of F, Cl, and cyano. In some embodiments of Formula (Ik-1),R^(2A) is H, R^(2B) is 3-oxetanyl, m is 2, each R^(1a) is independentlyselected from the group consisting of F, Cl, and —CF₃, p is 1, andR^(3a) is selected from the group consisting of F, Cl, and cyano. Insome embodiments of Formula (Ik-1), R^(2A) is methyl, R^(2B) is methyl,m is 2, each R^(1a) is independently selected from the group consistingof F, Cl, and —CF₃, p is 1, and R^(3a) is selected from the groupconsisting of F, Cl, and cyano.

In some embodiments of Formula (Ik-1), R^(2A) is H, R^(2B) is isopropyl,m is 2, each R^(1a) is independently selected from the group consistingof F, Cl, and —CF₃, p is 2, and each R^(3a) is independently selectedfrom the group consisting of F, Cl, and cyano. In some embodiments ofFormula (Ik-1), R^(2A) is H, R^(2B) is 3-oxetanyl, m is 2, each R^(1a)is independently selected from the group consisting of F, Cl, and —CF₃,p is 2, and each R^(3a) is independently selected from the groupconsisting of F, Cl, and cyano. In some embodiments of Formula (Ik-1),R^(2A) is methyl, R^(2B) is methyl, m is 2, each R^(1a) is independentlyselected from the group consisting of F, Cl, and —CF₃, p is 2, and eachR^(3a) is independently selected from the group consisting of F, Cl, andcyano.

In some embodiments of Formula (Ik-1): R^(2A) is H or methyl; R^(2B) isselected from the group consisting of isopropyl, —CHF₂, —CH(OH)CH₃,—CH₂OH, —CH₂CH₂SCH₃, —CH₂CH₂S(O)₂CH₃, —CH₂N(H)C(O)CH₃, —CH₂CH₂C(O)NH₂,methyl substituted with oxetanyl or azetidinyl, cyclopropyl, cyclobutyl,3-azetidinyl substituted with aminoacyl or acyl, 3-oxetanyl, 3-oxetanylsubstituted with methyl, tetrahydro-2H-pyranyl, and4-tetrahydro-2H-thiopyranyl; m is 1; R^(1a) is 4-F, 4-Cl, 4-methyl,4-CHF₂, and 4-CF₃; p is 2; and the two R^(3a) groups are selected fromthe group consisting of 3-F and 5-Cl, 3-F and 5-Br, 3-F and 5-cyano, 3-Fand 5-methyl, 3-F and 5-ethenyl, 3-F and 5-methoxy, 3-F and 5-OCH₃, 3-Fand 5-OCHF₂, and 3-methyl and 5-Cl.

In another aspect, the compound of Formula (I) is a compound of Formula(Ik-2), or a pharmaceutically acceptable salt thereof:

wherein G¹ is selected from the group consisting of substituted orunsubstituted cycloalkyl and substituted or unsubstituted heterocyclyl;each R^(1a) is independently selected from the group consisting of haloand substituted or unsubstituted alkyl; each R^(2a) is independentlyselected from the group consisting of substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted orunsubstituted acyl, substituted or unsubstituted aminothionyl,substituted or unsubstituted aminocarbonylamino, and substituted orunsubstituted alkyl; each R^(3a) is independently selected from thegroup consisting of halo, cyano, and substituted or unsubstituted alkyl;R⁴ is H; R⁵ is H or substituted or unsubstituted alkyl; m is 0, 1, or 2;n is 0, 1, or 2; and p is 0, 1, or 2.

In some embodiments of Formula (Ik-2), G¹ is substituted orunsubstituted cycloalkyl. In some embodiments of Formula (Ik-2), G¹ issubstituted or unsubstituted cyclopropyl. In some embodiments of Formula(Ik-2), G¹ is substituted or unsubstituted cyclobutanyl. In someembodiments of Formula (Ik-2), G¹ is substituted or unsubstituted4-membered to 6-membered heterocyclyl, which contains one or more (e.g.,1 or 2 or 3 or 1-4 or 1-3 or 2-4) of N or O atom. In some embodiments ofFormula (Ik-2), G¹ is substituted or unsubstituted 4-membered to6-membered heterocyclyl, which contains one N atom. In some embodimentsof Formula (Ik-2), G¹ is substituted or unsubstituted azetidinyl. Insome embodiments of Formula (Ik-2), G¹ is substituted or unsubstitutedpiperidinyl. In some embodiments of Formula (Ik-2), G¹ is substituted orunsubstituted 4-membered to 6-membered heterocyclyl, which contains oneO atom. In some embodiments of Formula (Ik-2), G¹ is substituted orunsubstituted oxetanyl. In some embodiments of Formula (Ik-2), G¹ issubstituted or unsubstituted tetrahydrofuranyl.

In some embodiments of Formula (Ik-2), m is 0. In some embodiments ofFormula (Ik-2), m is 1, and R^(1a) is selected from the group consistingof halo and substituted or unsubstituted alkyl. In some embodiments ofFormula (Ik-2), m is 1, and R^(1a) is on the 4-position of the phenylmoiety. In some embodiments of Formula (Ik-2), m is 1, and R^(1a) is4-F. In some embodiments of Formula (Ik-2), m is 1, and R^(1a) is 4-Cl.In some embodiments of Formula (Ik-2), m is 1, and R^(1a) is C₁-C₃ alkyloptionally substituted with halo. In some embodiments of Formula (Ik-2),m is 1, and R^(1a) is 4-methyl. In some embodiments of Formula (Ik-2), mis 1, and R^(1a) is 4-CHF₂. In some embodiments of Formula (Ik-2), m is1, and R^(1a) is 4-CF₃.

In some embodiments of Formula (Ik-2), n is 0. In some embodiments ofFormula (Ik-2), n is 1. In some embodiments of Formula (Ik-2), n is 2.

In some embodiments of Formula (Ik-2), each R^(2a) is independentlyselected from the group consisting of halo, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl,substituted or unsubstituted acyl, substituted or unsubstituted alkyl,and hydroxy. In some embodiments of Formula (Ik-2), R^(2a) is halo, suchas fluoro. In some embodiments of Formula (Ik-2), R^(2a) is substitutedor unsubstituted aryl. In some embodiments of Formula (Ik-2), R^(2a) issubstituted or unsubstituted phenyl. In some embodiments of Formula(Ik-2), R^(2a) is phenyl substituted with one or more (e.g., 1 or 2 or 3or 1-4 or 1-3 or 2-4) substituents selected from the group consisting ofhalo, alkoxycarbonyl, substituted or unsubstituted amino, andsubstituted or unsubstituted aminoacyl. In some embodiments of Formula(Ik-2), R^(2a) is phenyl substituted with halo. In some embodiments ofFormula (Ik-2), R^(2a) is phenyl substituted with alkoxycarbonyl. Insome embodiments of Formula (Ik-2), R^(2a) is phenyl substituted withmethoxycarbonyl. In some embodiments of Formula (Ik-2), R^(2a) is phenylsubstituted with substituted or unsubstituted amino. In some embodimentsof Formula (Ik-2), R^(2a) is phenyl substituted with methylamino. Insome embodiments of Formula (Ik-2), R^(2a) is phenyl substituted withsubstituted or unsubstituted aminoacyl. In some embodiments of Formula(Ik-2), R^(2a) is phenyl substituted with methylaminoacyl. In someembodiments of Formula (Ik-2), R^(2a) is phenyl substituted with twosubstituents selected from the group consisting of methoxycarbonyl,methylamino, and methylaminoacyl. In some embodiments of Formula (Ik-2),R^(2a) is substituted or unsubstituted heteroaryl. In some embodimentsof Formula (Ik-2), R^(2a) is substituted or unsubstituted oxadiazolyl.In some embodiments of Formula (Ik-2), R^(2a) is unsubstitutedoxadiazolyl. In some embodiments of Formula (Ik-2), R^(2a) isoxadiazolyl substituted with cycloalkyl. In some embodiments of Formula(Ik-2), R^(2a) is oxadiazolyl substituted with cyclopropyl. In someembodiments of Formula (Ik-2), R^(2a) is substituted or unsubstitutedpyridinyl. In some embodiments of Formula (Ik-2), R^(2a) isunsubstituted pyridinyl. In some embodiments of Formula (Ik-2), R^(2a)is pyridinyl substituted with halo, such as F. In some embodiments ofFormula (Ik-2), R^(2a) is pyridinyl substituted with cyano. In someembodiments of Formula (Ik-2), R^(2a) is substituted or unsubstitutedpyridin-2-yl. In some embodiments of Formula (Ik-2), R^(2a) issubstituted or unsubstituted alkoxycarbonyl. In some embodiments ofFormula (Ik-2), R^(2a) is methoxycarbonyl. In some embodiments ofFormula (Ik-2), R^(2a) is ethoxycarbonyl. In some embodiments of Formula(Ik-2), R^(2a) is substituted or unsubstituted aminoacyl. In someembodiments of Formula (Ik-2), R^(2a) is unsubstituted aminoacyl. Insome embodiments of Formula (Ik-2), R^(2a) is aminoacyl substituted withone or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituentsselected from the group consisting of C₁-C₃ alkyl, C₃-C₆ cycloalkyl, and4-membered to 7-membered heterocyclyl. In some embodiments of Formula(Ik-2), R^(2a) is aminoacyl substituted with C₁-C₃ alkyl. In someembodiments of Formula (Ik-2), R^(2a) is methylaminoacyl,ethylaminoacyl, or isopropylaminoacyl. In some embodiments of Formula(Ik-2), R^(2a) is dimethylaminoacyl. In some embodiments of Formula(Ik-2), R^(2a) is cyclopropylaminoacyl. In some embodiments of Formula(Ik-2), R^(2a) is tetrahydropyranylaminoacyl. In some embodiments ofFormula (Ik-2), R^(2a) is substituted or unsubstituted acyl. In someembodiments of Formula (Ik-2), R^(2a) is unsubstituted acyl. In someembodiments of Formula (Ik-2), R^(2a) is acyl substituted with one ormore (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected fromthe group consisting of substituted or unsubstituted alkyl andsubstituted or unsubstituted aryl. In some embodiments of Formula(Ik-2), R^(2a) is acyl substituted with methyl. In some embodiments ofFormula (Ik-2), R^(2a) is acyl substituted with phenyl, wherein thephenyl is optionally substituted with amino. In some embodiments ofFormula (Ik-2), R^(2a) is substituted or unsubstituted alkyl. In someembodiments of Formula (Ik-2), R^(2a) is C₁-C₃ alkyl substituted withhalo. In some embodiments of Formula (Ik-2), R^(2a) is ethyl substitutedwith two fluoro groups, such as —CH₂CHF₂. In some embodiments of Formula(Ik-2), R^(2a) is hydroxy.

In some embodiments of Formula (Ik-2), p is 0. In some embodiments ofFormula (Ik-2), p is 1. In some embodiments of Formula (Ik-2), p is 1,and R^(3a) is halo. In some embodiments of Formula (Ik-2), p is 1, andR^(3a) is 5-Cl. In some embodiments of Formula (Ik-2), p is 2. In someembodiments of Formula (Ik-2), p is 2, and each R^(3a) is independentlyhalo, cyano, or substituted or unsubstituted C₁-C₃ alkyl. In someembodiments of Formula (Ik-2), p is 2, and each R^(3a) is independentlyF, Cl, Br, cyano, or methyl. In some embodiments of Formula (Ik-2), p is2, and at least one R^(3a) is F or methyl. In some embodiments ofFormula (Ik-2), p is 2, and at least one R^(3a) is 3-F or 3-methyl. Insome embodiments of Formula (Ik-2), p is 2, and one R^(3a) is on the3-position of the pyridinyl moiety and is selected from the groupconsisting of F and methyl, and one R^(3a) is on the 5-position of thepyridinyl moiety and is selected from the group consisting of halo,cyano, and unsubstituted C₁-C₃ alkyl. In some embodiments of Formula(Ik-2), p is 2, and R^(3a) are 3-F and 5-Cl. In some embodiments ofFormula (Ik-2), p is 2, and R^(3a) are 3-F and 5-Br. In some embodimentsof Formula (Ik-1), p is 2, and R^(3a) are 3-F and 5-cyano. In someembodiments of Formula (Ik-2), p is 2, and R^(3a) are 3-methyl and 5-Cl.In some embodiments of Formula (Ik-2), p is 2, and R^(3a) are 3-methyland 5-cyano.

In some embodiments of Formula (Ik-2), R⁵ is H. In some embodiments ofFormula (Ik-2), R⁵ is substituted or unsubstituted alkyl. In someembodiments of Formula (Ik-2), R⁵ is methyl.

In some embodiments of Formula (Ik-2), G¹ is cyclobutanyl, m is 1,R^(1a) is selected the group consisting of F, Cl, and —CF₃, n is 0, p is1, R^(3a) is selected from the group consisting of F, Cl, and cyano, andR⁵ is H. In some embodiments of Formula (Ik-2), G¹ is azetidinyl, m is1, R^(1a) is selected from the group consisting of F, Cl, and —CF₃, n is0, p is 1, R^(3a) is selected from the group consisting of F, Cl, andcyano, and R⁵ is H. In some embodiments of Formula (Ik-2), G¹ isoxetanyl, m is 1, R^(1a) is selected from the group consisting of F, Cl,and —CF₃, n is 0, p is 1, R^(3a) is selected from the group consistingof F, Cl, and cyano, and R⁵ is H. In some embodiments of Formula (Ik-2),G¹ is cyclobutanyl, m is 1, R^(1a) is selected from the group consistingof F, Cl, and —CF₃, n is 0, p is 1, R^(3a) is selected from the groupconsisting of F, Cl, and cyano, and R⁵ is methyl. In some embodiments ofFormula (Ik-2), G¹ is azetidinyl, m is 1, R^(1a) is selected from thegroup consisting of F, Cl, and —CF₃, n is 0, p is 1, R^(3a) is selectedfrom the group consisting of F, Cl, and cyano, and R⁵ is methyl. In someembodiments of Formula (Ik-2), G¹ is oxetanyl, m is 1, R^(1a) isselected from the group consisting of F, Cl, and —CF₃, n is 0, p is 1,R^(3a) is selected from the group consisting of F, Cl, and cyano, and R⁵is methyl.

In some embodiments of Formula (Ik-2), G¹ is cyclobutanyl, m is 1,R^(1a) is selected from the group consisting of F, Cl, and —CF₃, n is 0,p is 2, each R^(3a) is independently selected from the group consistingof F, Cl, and cyano, and R⁵ is H. In some embodiments of Formula (Ik-2),G¹ is azetidinyl, m is 1, R^(1a) is selected from the group consistingof F, Cl, and —CF₃, n is 0, p is 2, each R^(3a) is independentlyselected from the group consisting of F, Cl, and cyano, and R⁵ is H. Insome embodiments of Formula (Ik-2), G¹ is oxetanyl, m is 1, R^(1a) isselected from the group consisting of F, Cl, and —CF₃, n is 0, p is 2,each R^(3a) is independently selected from the group consisting of F,Cl, and cyano, and R⁵ is H. In some embodiments of Formula (Ik-2), G¹ iscyclobutanyl, m is 1, R^(1a) is selected from the group consisting of F,Cl, and —CF₃, n is 0, p is 2, each R^(3a) is independently selected fromthe group consisting of F, Cl, and cyano, and R⁵ is methyl. In someembodiments of Formula (Ik-2), G¹ is azetidinyl, m is 1, R^(1a) isselected from the group consisting of F, Cl, and —CF₃, n is 0, p is 2,each R^(3a) is independently selected from the group consisting of F,Cl, and cyano, and R⁵ is methyl. In some embodiments of Formula (Ik-2),G¹ is oxetanyl, m is 1, R^(1a) is selected from the group consisting ofF, Cl, and —CF₃, n is 0, p is 2, each R^(3a) is independently selectedfrom the group consisting of F, Cl, and cyano, and R⁵ is methyl.

In some embodiments of Formula (Ik-2), G¹ is cyclobutanyl, m is 2, eachR^(1a) is independently selected from the group consisting of F, Cl, and—CF₃, n is 0, p is 1, R^(3a) is selected from the group consisting of F,Cl, and cyano, and R⁵ is H. In some embodiments of Formula (Ik-2), G¹ isazetidinyl, m is 2, each R^(1a) is independently selected from the groupconsisting of F, Cl, and —CF₃, n is 0, p is 1, R^(3a) is selected fromthe group consisting of F, Cl, and cyano, and R⁵ is H. In someembodiments of Formula (Ik-2), G¹ is oxetanyl, m is 2, each R^(1a) isindependently selected from the group consisting of F, Cl, and —CF₃, nis 0, p is 1, R^(3a) is selected from the group consisting of F, Cl, andcyano, and R⁵ is H. In some embodiments of Formula (Ik-2), G¹ iscyclobutanyl, m is 2, each R^(1a) is independently selected from thegroup consisting of F, Cl, and —CF₃, n is 0, p is 1, R^(3a) is selectedfrom the group consisting of F, Cl, and cyano, and R⁵ is methyl. In someembodiments of Formula (Ik-2), G¹ is azetidinyl, m is 2, each R^(1a) isindependently selected from the group consisting of F, Cl, and —CF₃, nis 0, p is 1, R^(3a) is selected from the group consisting of F, Cl, andcyano, and R⁵ is methyl. In some embodiments of Formula (Ik-2), G¹ isoxetanyl, m is 2, each R^(1a) is independently selected from the groupconsisting of F, Cl, and —CF₃, n is 0, p is 1, R^(3a) is selected fromthe group consisting of F, Cl, and cyano, and R⁵ is methyl.

In some embodiments of Formula (Ik-2), G¹ is cyclobutanyl, m is 2, eachR^(1a) is independently selected from the group consisting of F, Cl, and—CF₃, n is 0, p is 2, each R^(3a) is independently selected from thegroup consisting of F, Cl, and cyano, and R⁵ is H. In some embodimentsof Formula (Ik-2), G¹ is azetidinyl, m is 2, each R^(1a) isindependently selected from the group consisting of F, Cl, and —CF₃, nis 0, p is 2, each R^(3a) is independently selected from the groupconsisting of F, Cl, and cyano, and R⁵ is H. In some embodiments ofFormula (Ik-2), G¹ is oxetanyl, m is 2, each R^(1a) is independentlyselected from the group consisting of F, Cl, and —CF₃, n is 0, p is 2,each R^(3a) is independently selected from the group consisting of F,Cl, and cyano, and R⁵ is H. In some embodiments of Formula (Ik-2), G¹ iscyclobutanyl, m is 2, each R^(1a) is independently selected from thegroup consisting of F, Cl, and —CF₃, n is 0, p is 2, each R^(3a) isindependently selected from the group consisting of F, Cl, and cyano,and R⁵ is methyl. In some embodiments of Formula (Ik-2), G¹ isazetidinyl, m is 2, each R^(1a) is independently selected from the groupconsisting of F, Cl, and —CF₃, n is 0, p is 2, each R^(3a) isindependently selected from the group consisting of F, Cl, and cyano,and R⁵ is methyl. In some embodiments of Formula (Ik-2), G¹ is oxetanyl,m is 2, each R^(1a) is independently selected from the group consistingof F, Cl, and —CF₃, n is 0, p is 2, each R^(3a) is independentlyselected from the group consisting of F, Cl, and cyano, and R⁵ ismethyl.

In another aspect, the compound of Formula (I) is a compound of Formula(Il), or a pharmaceutically acceptable salt thereof:

wherein R^(2A) is H or substituted or unsubstituted alkyl; R^(2b) isselected from the group consisting of H, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted aminoacyl, and hydroxy; m is 0, 1, or 2; p is 0, 1, or 2;each R^(1a) is independently selected from the group consisting of haloand substituted or unsubstituted alkyl; each R^(3a) is independentlyhalo; and R⁴ is H.

In some embodiments of Formula (Il), R^(2A) is H.

In some embodiments of Formula (Il), R^(2b) is selected from the groupconsisting of substituted or unsubstituted alkyl, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl,and hydroxy. In some embodiments of Formula (Il), R^(2b) is selectedfrom the group consisting of substituted or unsubstituted alkyl,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted aminoacyl, and hydroxy. In some embodiments of Formula(Il), R^(2b) is selected from the group consisting of substituted C₁-C₃alkyl, unsubstituted C₁-C₃ alkoxycarbonyl, unsubstituted aminoacyl, andhydroxy. In some embodiments of Formula (Il), R^(2b) is C₁-C₃ alkylsubstituted with hydroxy. In some embodiments of Formula (Il), R^(2b) is—CH₂OH. In some embodiments of Formula (Il), R^(2b) is methoxycarbonyl.In some embodiments of Formula (Il), R^(2b) is ethoxycarbonyl. In someembodiments of Formula (Il), R^(2b) is unsubstituted aminoacyl. In someembodiments of Formula (Il), R^(2b) is hydroxy.

In some embodiments of Formula (Il), m is 1, and R^(1a) is selected fromthe group consisting of halo and substituted or unsubstituted alkyl. Insome embodiments of Formula (Il), m is 1, and R^(1a) is on the4-position of the phenyl moiety. In some embodiments of Formula (Il), mis 1, and R^(1a) is 4-F. In some embodiments of Formula (Il), m is 1,and R^(1a) is 4-Cl. In some embodiments of Formula (Il), m is 1, andR^(1a) is C₁-C₃ alkyl optionally substituted with halo. In someembodiments of Formula (Il), m is 1, and R^(1a) is 4-methyl. In someembodiments of Formula (Il), m is 1, and R^(1a) is 4-CHF₂. In someembodiments of Formula (Il), m is 1, and R^(1a) is 4-CF₃.

In some embodiments of Formula (Il), p is 2, and each R^(3a) isindependently halo. In some embodiments of Formula (Il), p is 2, andeach R^(3a) is independently F or Cl. In some embodiments of Formula(Il), p is 2, and one R^(3a) is 3-halo and one R^(3a) is 5-halo. In someembodiments of Formula (Il), p is 2, and R^(3a) are 3-F and 5-Cl.

In another aspect, the compound of Formula (I) is a compound of Formula(Im), or a pharmaceutically acceptable salt thereof:

wherein Q is —O— or —N(R^(2b))—; R^(2b) is selected from the groupconsisting of H and substituted or unsubstituted acyl; m is 0, 1, or 2;p is 0, 1, or 2; each R^(1a) is independently selected from the groupconsisting of halo and substituted or unsubstituted alkyl; each R^(3a)is independently halo; and R⁴ is H.

In some embodiments of Formula (Im), Q is —O—. In some embodiments ofFormula (Im), Q is —N(R^(2b))—.

In some embodiments of Formula (Im), R^(2b) is substituted orunsubstituted acyl. In some embodiments of Formula (Im), R^(2b) isunsubstituted acyl. In some embodiments of Formula (Im), R^(2b) is acylsubstituted with alkyl. In some embodiments of Formula (Im), R^(2b) isacyl substituted with methyl.

In some embodiments of Formula (Im), m is 1, and R^(1a) is selected fromthe group consisting of halo and substituted or unsubstituted alkyl. Insome embodiments of Formula (Im), m is 1, and R^(1a) is on the4-position of the phenyl moiety. In some embodiments of Formula (Im), mis 1, and R^(1a) is 4-F. In some embodiments of Formula (Im), m is 1,and R^(1a) is 4-Cl. In some embodiments of Formula (Im), m is 1, andR^(1a) is C₁-C₃ alkyl optionally substituted with halo. In someembodiments of Formula (Im), m is 1, and R^(1a) is 4-methyl. In someembodiments of Formula (Im), m is 1, and R^(1a) is 4-CHF₂. In someembodiments of Formula (Im), m is 1, and R^(1a) is 4-CF₃.

In some embodiments of Formula (Im), p is 2, and each R^(3a) isindependently halo. In some embodiments of Formula (Im), p is 2, andeach R^(3a) is independently F or C₁. In some embodiments of Formula(Im), p is 2, and one R^(3a) is 3-halo and one R^(3a) is 5-halo. In someembodiments of Formula (Im), p is 2, and R^(3a) are 3-F and 5-C₁.

In another aspect, the compound of Formula (I) is a compound of Formula(In-1) or Formula (In-2), or a pharmaceutically acceptable salt thereof:

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedphenyl and substituted or unsubstituted pyridyl;

-   -   R^(2A), R^(2B), and R³ are defined by any one of (i)-(iii):    -   (i) R^(2A) is H or substituted or unsubstituted alkyl;        -   R^(2B) is selected from the group consisting of H,            substituted or unsubstituted alkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted cycloalkenyl, substituted or unsubstituted            cycloalkynyl, substituted or unsubstituted heterocyclyl,            substituted or unsubstituted aryl, and substituted or            unsubstituted heteroaryl; and        -   R³ is substituted or unsubstituted phenyl or substituted or            unsubstituted pyridyl;    -   or    -   (ii) R^(2A) is H or substituted or unsubstituted alkyl;        -   R^(2B) is substituted or unsubstituted phenyl or substituted            or unsubstituted pyridyl; and        -   R³ is substituted or unsubstituted alkyl;    -   or    -   (iii) R^(2A) and R^(2B) are taken together with the carbon atom        to which they are attached to form G¹, wherein G¹ is a        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted cycloalkenyl, substituted or unsubstituted        cycloalkynyl, or substituted or unsubstituted heterocyclyl ring,        each of which is optionally fused to a phenyl ring; and        -   R³ is selected from the group consisting of substituted or            unsubstituted alkyl, substituted or unsubstituted alkenyl,            substituted or unsubstituted alkynyl, substituted or            unsubstituted cycloalkyl, substituted or unsubstituted            cycloalkenyl, substituted or unsubstituted cycloalkynyl,            substituted or unsubstituted heterocyclyl, substituted or            unsubstituted aryl, and substituted or unsubstituted            heteroaryl;    -   R⁴ is H or substituted or unsubstituted alkyl; and    -   R⁵ is H or substituted or unsubstituted alkyl;        wherein, when one or more of provisions (a)-(c) apply, then R¹        is substituted or unsubstituted pyridyl or phenyl substituted        with at least one substituent other than methyl or methoxy:    -   (a) R^(2A) and R^(2B) are as defined by (i) and R³ is        substituted or unsubstituted phenyl;    -   (b) R^(2A) and R³ are as defined by (ii) and R^(2B) is        4-methoxyphenyl;    -   (c) R^(2A), and R^(2B)— are as defined by (iii) and R³ is        4-methoxyphenylmethyl.

In some embodiments, provided herein are compounds and salts thereofdescribed in Table 1.

TABLE 1 No. Structure Name 1

N-cyclobutyl-9-isopropyl- 7,10-dioxo-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]- decane-2-carboxamide 2

5-(4-chlorobenzyl)-8- isopropyl-2-phenyl-2,5,8- triazaspiro[3.5]nonane-6,9-dione 3

5-(4-chlorobenzyl)-2-(4- fluorophenyl)-8-isopropyl-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 4

5-(4-chlorobenzyl)-2-(4- chlorophenyl)-8-isopropyl-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 5

5-(4-chlorobenzyl)-2-(3- chlorophenyl)-8-isopropyl-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 6

5-(4-chlorobenzyl)-8- isopropyl-2-(pyridin-2-yl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 7

5-(4-chlorobenzyl)-8- isopropyl-2-(pyridin-3-yl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 8

5-(4-chlorobenzyl)-8- isopropyl-2-(pyridin-4-yl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 9

5-(4-chlorobenzyl)-8- isopropyl-2-(5-methyl- pyridin-2-yl)-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 10

5-(4-chlorobenzyl)-8- isopropyl-2-(2-methyl- pyridin-4-yl)-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 11

5-(4-chlorobenzyl)-8- isopropyl-2-(pyrimidin- 2-yl)-2,5,8-triazaspiro-[3.5]nonane-6,9-dione 12

5-(4-chlorobenzyl)-8- isopropyl-2-(pyrazin- 2-yl)-2,5,8-triazaspiro-[3.5]nonane-6,9-dione 13

5-(4-chlorobenzyl)-8- isopropyl-2-(2-methyl- pyridin-3-yl)-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 14

5-(4-chlorobenzyl)-8- isopropyl-2-(6-methyl- pyridin-3-yl)-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 15

5-(4-chlorobenzyl)-8- isopropyl-2-(4-methyl- pyridin-2-yl)-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 16

5-(4-chlorobenzyl)-8- isopropyl-2-(5-methyl- pyridin-3-yl)-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 17

5-(4-chlorobenzyl)-2-(5- fluoropyridin-2-yl)-8- isopropyl-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 18

5-(4-chlorobenzyl)-2-(5- fluoropyridin-3-yl)-8- isopropyl-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 19

5-(4-chlorobenzyl)-8- isopropyl-2-(pyrimidin- 4-yl)-2,5,8-triazaspiro-[3.5]nonane-6,9-dione 20

5-(4-chlorobenzyl)-2- (4-fluorophenyl)-8- isopropyl-7-methyl-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 21

5-(4-chlorobenzyl)-8- isopropyl-2-(1-methyl- 1H-pyrazol-4-yl)-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 22

5-(4-chlorobenzyl)-8- isopropyl-2-(thiazol-2-yl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 23

5-(4-chlorobenzyl)-8- isopropyl-2-(pyridazin-3-yl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 24

5-(4-chlorobenzyl)-8- isopropyl-2-(pyridazin-4-yl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 25

5-(4-chlorobenzyl)-8- isopropyl-2-(pyrimidin- 5-yl)-2,5,8-triazaspiro-[3.5]nonane-6,9-dione 26

5-(4-chlorobenzyl)-8- isopropyl-2-(5-methyl- 1H-pyrazol-3-yl)-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 27

4-(5-(4-chlorobenzyl)-8- isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonan- 2-yl)picolinonitrile 28

5-(4-chlorobenzyl)-2-(2- hydroxypyridin-4-yl)-8- isopropyl-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 29

5-(4-chlorobenzyl)-2-(2- (difluoromethyl)pyridin-4-yl)-8-isopropyl-2,5,8- triazaspiro[3.5]nonane- 6,9-dione 30

8-isopropyl-5-(4- methylbenzyl)-2-(2- methylpyridin-4-yl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 31

8-isopropyl-2-(2- methylpyridin-4-yl)-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 32

5-(4-chlorobenzyl)-8- isopropyl-2-(thiazol-4-yl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 33

5-(4-chlorobenzyl)-8- isopropyl-2-(thiazol-5-yl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 34

5-(4-chlorobenzyl)-2-(2- cyclopropylpyridin-4-yl)- 8-isopropyl-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 35

methyl 4-(5-(4-chloro- benzyl)-8-isopropyl- 6,9-dioxo-2,5,8-triazaspiro[3.5]nonan- 2-yl)picolinate 36

4-(5-(4-chlorobenzyl)-8- isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonan-2- yl)picolinic acid 37

4-(5-(4-chlorobenzyl)-8- isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonan-2- yl)picolinamide 38

4-(5-(4-chlorobenzyl)-8- isopropyl-6,9-dioxo- 2,5,8-triazaspiro-[3.5]nonan-2-yl)-N- methylpicolinamide 39

5-(4-chlorobenzyl)-8- isopropyl-2-(4- (trifluoromethyl)thiazol-2-yl)-2,5,8-triazaspiro- [3.5]nonane-6,9-dione 40

2-(5-(4-chlorobenzyl)-8- isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonan-2- yl)thiazole-4-carboxamide 41

5-(4-chlorobenzyl)-8- isopropyl-2-(1H-pyrazol- 4-yl)-2,5,8-triazaspiro-[3.5]nonane-6,9-dione 42

5-(4-chlorobenzyl)-8- isopropyl-2-(1-methyl- 2-oxo-1,2-dihydropyridin-4-yl)-2,5,8-triazaspiro- [3.5]nonane-6,9-dione 43

5-(4-chlorobenzyl)-8- isopropyl-2-(4-methyl- thiazol-2-yl)-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 44

5-(4-chlorobenzyl)-8- isopropyl-2-(5-methyl- thiazol-2-yl)-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 45

5-(4-chlorobenzyl)-8- isopropyl-2-(5-methyl- 1,3,4-oxadiazol-2-yl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 46

8-isopropyl-2-(pyridin-2- yl)-5-(4-(trifluoromethyl)-benzyl)-2,5,8-triazaspiro- [3.5]nonane-6,9-dione 47

5-(4-chlorobenzyl)-2-(6,7- dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-8-isopropyl- 2,5,8-triazaspiro[3.5]- nonane-6,9-dione 48

8-isopropyl-2-(2-oxo-1,2- dihydropyridin-4-yl)-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-6,9-dione 49

5-(4-chlorobenzyl)-2-(2,6- dimethylpyridin-4-yl)-8- isopropyl-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 50

5-(4-chlorobenzyl)-2-(6- chloropyridazin-3-yl)-8- isopropyl-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 51

5-(4-chlorobenzyl)-8- isopropyl-2-(6- methoxypyridazin-3-yl)-2,5,8-triazaspiro- [3.5]nonane-6,9-dione 52

5-(4-chlorobenzyl)-8- isopropyl-2-(6-oxo-1,6- dihydropyridazin-3-yl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 53

5-(4-chlorobenzyl)-8- isopropyl-2-(6- (trifluoromethyl)pyridazin-3-yl)-2,5,8-triazaspiro- [3.5]nonane-6,9-dione 54

6-(5-(4-chlorobenzyl)-8- isopropyl-6,9-dioxo- 2,5,8-triazaspiro[3.5]-nonan-2-yl)pyridazine- 3-carboxamide 55

5-(4-chlorobenzyl)-8- isopropyl-2-(6- methylpyridazin-3-yl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 56

5-(4-chlorobenzyl)-2-(5- chloropyrazin-2-yl)-8- isopropyl-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 57

6-(8-ethyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonan-2-yl)nicotinonitrile 58

6-(8-cyclopentyl-6,9- dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonan-2-yl)nicotinonitrile 59

6-(8-isobutyl-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonan-2-yl)nicotinonitrile 60

5-(4-chlorobenzyl)-2-(5- chloropyridazin-3-yl)- 8-isopropyl-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 61

5-(4-chlorobenzyl)-2-(6- chloropyridazin-4-yl)-8- isopropyl-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 62

6-(8-cydohexyl-6,9-dioxo- 5-(4-(trifluoromethyl)- benzyl)-2,5,8-triazaspiro[3.5]nonan- 2-yl)nicotinonitrile 63

6-(5-(4-chlorobenzyl)-8- isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonan-2- yl)nicotinonitrile 64

methyl 5-(4-chlorobenzyl)- 8-isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]- nonane-2-carboxylate 65

5-(4-chlorobenzyl)-8- isopropyl-N-methyl-6,9- dioxo-2,5,8-triazaspiro-[3.5]nonane-2- carboxamide 66

5-(4-chlorobenzyl)-8- isopropyl-N-(1-methyl-1H- pyrazol-4-yl)-6,9-dioxo-2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 67

8-isopropyl-N-methyl-6,9- dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 68

8-isopropyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 69

8-isopropyl-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carbaldehyde 70

8-cyclopentyl-N-methyl- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 71

6-(4-chlorobenzyl)-9- isopropyl-2-(pyrimidin-4- yl)-2,6,9-triazaspiro-[4.5]decane-7,10-dione 72

9-isopropyl-2-(2- methylpyridin-4-yl)-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 73

9-isopropyl-2-(pyridazin- 3-yl)-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 74

6-(4-chlorobenzyl)-9- isopropyl-2-(pyrazin-2-yl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 75

6-(4-chlorobenzyl)-9- isopropyl-2-(5- methylpyridin-2-yl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 76

9-isopropyl-2-(2-oxo-1,2- dihydropyridin-4-yl)-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]- decane-7,10-dione 77

2-(2,6-dimethylpyridin-4- yl)-9-isopropyl-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]- decane-7,10-dione 78

6-(4-chlorobenzyl)-9- isopropyl-2-(1-methyl-1H- pyrazol-4-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 79

6-(4-chlorobenzyl)-9- isopropyl-2-(pyridazin-3-yl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 80

6-(4-chlorobenzyl)-9- isopropyl-2-(1-methyl-2- oxo-1,2-dihydropyridin-4-yl)-2,6,9-triazaspiro- [4.5]decane-7,10-dione 81

6-(4-chlorobenzyl)-9- isopropyl-2-(2-oxo-1,2-dihydropyridin-4-yl)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 82

6-(4-chlorobenzyl)-9-ethyl- 2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 83

6-(4-chlorobenzyl)-9- cyclopentyl-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 84

6-(4-chlorobenzyl)-9- isobutyl-2-(pyridin-2-yl)- 2,6,9-triazaspiro[4.5]-decane-7,10-dione 85

6-(4-chlorobenzyl)-9-(1- methylcyclopropyl)-2- (pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 86

6-(4-chlorobenzyl)-9-(1- methoxypropan-2-yl)-2- (pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 87

6-(4-chlorobenzyl)-9- isopropyl-2-(2- methoxypyridin-4-yl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 88

2-(9-isopropyl-7,10-dioxo- 6-(4-(trifluoromethyl)- benzyl)-2,6,9-triazaspiro[4.5]decan-2- yl)isonicotinonitrile 89

2-(9-isopropyl-7,10-dioxo- 6-(4-(trifluoromethyl)- benzyl)-2,6,9-triazaspiro[4.5]decan- 2-yl)isonicotinamide 90

6-(6-(3,4-dichlorobenzyl)- 9-isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]- decan-2-yl)nicotinonitrile 91

6-(6-(3,4-dichlorobenzyl)- 9-isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decan- 2-yl)nicotinamide 92

6-(4-chlorobenzyl)-2-(5- fluoropyridin-2-yl)-9- isopropyl-2,6,9-triazaspiro[4.5]decane- 7,10-dione 93

6-(4-chlorobenzyl)-2- (pyridin-2-yl)-9-((R)- tetrahydrofuran-3-yl)-2,6,9-triazaspiro- [4.5]decane-7,10-dione 94

6-(4-chlorobenzyl)-2- (pyridin-2-yl)-9-((S)-tetra-hydrofuran-3-yl)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 95

2-(6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decan-2- yl)isonicotinonitrile 96

6-(6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decan-2- yl)nicotinonitrile 97

2-(6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decan-2- yl)isonicotinamide 98

6-(6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decan-2- yl)nicotinamide 99

(S)-6-(4-chlorobenzyl)-9- isopropyl-2-(pyrimidin-4-yl)-2,6,9-triazaspiro- [4.5]decane-7,10-dione 100

(S)-6-(4-chlorobenzyl)-9- isopropyl-2-(pyrazin-2-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 101

(S)-6-(4-chlorobenzyl)-9- isopropyl-2-(5-methylpyridin-2-yl)-2,6,9-triazaspiro- [4.5]decane-7,10-dione 102

(S)-6-(4-chlorobenzyl)-2-(5- fluoropyridin-2-yl)-9-isopropyl-2,6,9-triazaspiro- [4.5]decane-7,10-dione 103

(S)-6-(4-chlorobenzyl)-9- isopropyl-2-(pyridazin-3-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 104

(S)-6-(4-chlorobenzyl)-9- isopropyl-2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)- 2,6,9-triazaspiro[4.5]- decane-7,10-dione 105

(S)-6-(4-chlorobenzyl)-9- isopropyl-2-(2-oxo-1,2-dihydropyridin-4-yl)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 106

(S)-6-(4-chlorobenzyl)-9- isopropyl-2-(1-methyl-1H- pyrazol-4-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 107

9-isopropyl-7,10-dioxo-6- (4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane- 2-carboxamide 108

9-isopropyl-N-methyl-7,10- dioxo-6-(4-(trifluoro- methyl)-benzyl)-2,6,9-triazaspiro[4.5]-decane- 2-carboxamide 109

9-isopropyl-7,10-dioxo- N-phenyl-6-(4-(trifluoro- methyl)benzyl)-2,6,9-triazaspiro[4.5]decane- 2-carboxamide 110

methyl 9-isopropyl-7,10- dioxo-6-(4-(trifluoro- methyl)benzyl)-2,6,9-triazaspiro[4.5]decane- 2-carboxylate 111

9-isopropyl-7,10-dioxo-N- (pyridin-4-yl)-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]- decane-2-carboxamide 112

N-(tert-butyl)-9-isopropyl- 7,10-dioxo-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]- decane-2-carboxamide 113

9-isopropyl-7,10-dioxo-N- (pyridin-3-yl)-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]- decane-2-carboxamide 114

9-isopropyl-N-(1-methyl-1H- pyrazol-4-yl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]decane- 2-carboxamide115

N-(4-fluorophenyl)-9- isopropyl-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]decane- 2-carboxamide116

N-ethyl-9-isopropyl-7,10- dioxo-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5] decane-2-carboxamide 117

N,9-diisopropyl-7,10-dioxo-6- (4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane- 2-carboxamide 118

N-cyclopropyl-9-isopropyl- 7,10-dioxo-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane- 2-carboxamide 119

6-(4-chlorobenzyl)-N-ethyl- 9-isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]- decane-2-carboxamide 120

6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2- carboxamide 121

6-(4-chlorobenzyl)-9- isopropyl-N-methyl-7,10-dioxo-2,6,9-triazaspiro[4.5]- decane-2-carboxamide 122

6-(4-chlorobenzyl)-N- cyclopropyl-9-isopropyl- 7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2- carboxamide 123

6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-N- phenyl-2,6,9-triazaspiro-[4.5]decane-2-carboxamide 124

(S)-6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2- carboxamide 125

(S)-6-(4-chlorobenzyl)-N- cydopropyl-9-isopropyl-7,10-dioxo-2,6,9-triazaspiro- [4.5]decane-2-carboxamide 126

(S)-6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-N-phenyl-2,6,9-triazaspiro- [4.5]decane-2-carboxamide 127

6-(4-chlorobenzyl)-9- isopropyl-2-phenyl-2,6,9- triazaspiro[4.5]decane-7,10-dione 128

6-(4-chlorobenzyl)-9- isopropyl-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 129

6-(4-chlorobenzyl)-9- isopropyl-2-(2-methyl- pyridin-4-yl)-2,6,9-triazaspiro-[4.5]decane- 7,10-dione 130

(S)-6-(4-chlorobenzyl)- 9-isopropyl-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 131

(S)-6-(4-chlorobenzyl)-9- isopropyl-2-phenyl-2,6,9-triazaspiro[4.5]decane- 7,10-dione 132

(S)-6-(4-chlorobenzyl)-9- isopropyl-2-(2-methyl- pyridin-4-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 133

(S)-6-(4-chlorobenzyl)-9- isopropyl-N-methyl-7,10-dioxo-2,6,9-triazaspiro- [4.5]decane-2-carboxamide 134

(S)-6-(4-chlorobenzyl)-N- ethyl-9-isopropyl-7,10-dioxo-2,6,9-triazaspiro- [4.5]decane-2-carboxamide 135

(S)-6-(4-chlorobenzyl)- N,9-diisopropyl-7,10- dioxo-2,6,9-triazaspiro-[4.5]decane-2-carboxamide 136

(S)-6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-N- (pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane-2- carboxamide 137

(S)-6-(4-chlorobenzyl)-9- isopropyl-N-(2- methoxyethyl)-7,10-dioxo-2,6,9-triazaspiro- [4.5]decane-2-carboxamide 138

8-isopropyl-2-(pyridin-2-yl)- 5-(1-(4-(trifluoromethyl)-phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonane- 6,9-dione 139

8-isopropyl-N-methyl-6,9- dioxo-5-(1-(4- (trifluoromethyl)phenyl)-ethyl)-2,5,8-triazaspiro- [3.5]nonane-2-carboxamide 140

8-isopropyl-2-phenyl-5-(1- (4-(trifluoromethyl)phenyl)-ethyl)-2,5,8-triazaspiro- [3.5]nonane-6,9-dione 141

(R)-8-isopropyl-2-phenyl-5- (1-(4-(trifluoromethyl)-phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonane- 6,9-dione 142

(S)-8-isopropyl-2-phenyl-5- (1-(4-(trifluoromethyl)-phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonane- 6,9-dione 143

(S)-6-((S)-1-(4- chlorophenyl)ethyl)-9- isopropyl-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 144

(R)-6-((S)-1-(4- chlorophenyl)ethyl)-9- isopropyl-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 145

8-(4-methoxyphenyl)-N- methyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 146

8-(4-cyanophenyl)-N-methyl- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 147

8-(6-cyanopyridin-3-yl)-N- methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-2-carboxamide148

methyl 4-(2- (methylcarbamoyl)-6,9- dioxo-5-(4-(trifluoro-methyl)benzyl)-2,5,8- triazaspiro[3.5]nonan-8- yl)benzoate 149

8-(4-fluorophenyl)-N-methyl- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 150

8-(4-chlorophenyl)-N- methyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 151

N-methyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-8-(4-(trifluoromethyl)phenyl)- 2,5,8-triazaspiro[3.5]nonane- 2-carboxamide152

8-(3,4-difluorophenyl)-N- methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonane- 2-carboxamide153

N-methyl-6,9-dioxo-8- (p-tolyl)-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 154

8-(6-methoxypyridin-3-yl)- N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-2-carboxamide155

8-(4-chloro-3-fluorophenyl)- N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-2-carboxamide156

8-(5-chloropyridin-2-yl)-N- methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-2-carboxamide157

8-(4-(difluoromethyl)- phenyl)-N-methyl-6,9-dioxo-5(4-(trifluoromethyl)- benzyl)-2,5,8-triazaspiro-[3.5]nonane-2-carboxamide 158

8-(4-cyclopropylphenyl)- N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-2-carboxamide159

8-(4-(difluoromethoxy)- phenyl)-N-methyl-6,9- dioxo-5-(4-(trifluoro-methyl)benzyl)-2,5,8- triazaspiro[3.5]nonane- 2-carboxamide 160

N-methyl-6,9-dioxo-8- (4-(trifluoromethoxy)- phenyl)-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-2-carboxamide161

N-methyl-6,9-dioxo-8-(4- (prop-1-en-2-yl)phenyl)-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]-nonane-2-carboxamide 162

8-(4-cyano-3-fluorophenyl)- N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-2-carboxamide163

8-(3-chlorophenyl)-N- methyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 164

5-(4-chlorobenzyl)-8-(4- cyanophenyl)-N-methyl-6,9-dioxo-2,5,8-triazaspiro- [3.5]nonane-2-carboxamide 165

8-(4-(5-(difluoromethyl)- 1,2,4-oxadiazol-3-yl)- phenyl)-N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-2,5,8-triazaspiro-[3.5]nonane-2-carboxamide 166

8-(4-chloro-3-methyl- phenyl)-N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-2,5,8-triazaspiro-[3.5]nonane-2-carboxamide 167

8-(4-cyano-3-methyl- phenyl)-N-methyl-6,9- dioxo-5-(4-(trifluoromethyl)-benzyl)-2,5,8-triazaspiro- [3.5]nonane-2-carboxamide 168

8-(4-chloro-2-fluoro- phenyl)-N-methyl-6,9- dioxo-5-(4-(trifluoro-methyl)benzyl)-2,5,8- triazaspiro[3.5]nonane- 2-carboxamide 169

8-(4-cyano-2-fluoro- phenyl)-N-methyl-6,9- dioxo-5-(4-(trifluoromethyl)-benzyl)-2,5,8-triazaspiro- [3.5]nonane-2-carboxamide 170

8-(3-fluoro-4-methoxy- phenyl)-N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-2,5,8-triazaspiro-[3.5]nonane-2-carboxamide 171

8-(4-(difluoromethoxy)-3- fluorophenyl)-N-methyl- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5/8-triazaspiro[3.5]- nonane-2-carboxamide172

8-(4-benzoylphenyl)-N- methyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 173

8-(4-cyano-2-fluorophenyl)- N-methyl-6,9-dioxo-5-(4-(3-(trifluoromethyl)-3H- diazirin-3-yl)benzyl)-2,5,8-triazaspiro[3.5]nonane- 2-carboxamide 174

3-fluoro-4-(2-isobutyryl- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 8-yl)benzonitrile 175

4-(2-acetyl-5-(4- chlorobenzyl)-6,9-dioxo- 2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile 176

4-(2-acetyl-5-(4-fluoro- benzyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonan-8-yl)- 3-fluorobenzonitrile 177

N-methyl-6,9-dioxo-8-(2- oxo-2H-chromen-6-yl)-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-2-carboxamide178

8-(4-ethynyl-2-fluoro- phenyl)-N-methyl-6,9- dioxo-5-(4-(3-(trifluoromethyl)-3H- diazirin-3-yl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2- carboxamide 179

3-fluoro-4-(2-formyl-6,9- dioxo-5-(4-(trifluoro- methyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8- yl)benzonitrile 180

4-(2-(cyclobutanecarbonyl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 8-yl)-3-fluorobenzonitrile 181

N-methyl-6,9-dioxo-8-(2- oxo-2H-chromen-6-yl)-5-(4-(3-(trifluoromethyl)- 3H-diazirin-3-yl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 182

2-acetyl-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4- chlorobenzyl)-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 183

9-(4-cyanophenyl)-N- methyl-7,10-dioxo-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]- decane-2-carboxamide 184

9-(6-cyanopyridin-3-yl)-N- methyl-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]- decane-2-carboxamide185

6-(4-chlorobenzyl)-9-(4- cyanophenyl)-N-methyl- 7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2- carboxamide 186

4-(2-acetyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 8-yl)benzonitrile 187

4-(6,9-dioxo-2-propionyl-5- (4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 8-yl)benzonitrile 188

methyl 8-(4-cyanophenyl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carboxylate 189

8-(4-cyanophenyl)-N- methyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carbothioamide 190

4-(2-formyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 8-yl)benzonitrile 191

4-(2-(2,2-difluoroethyl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 8-yl)benzonitrile 192

6-(8-(4-cyanophenyl)-6,9- dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 2-yl)nicotinonitrile 193

4-(2-(2,2-difluoroethyl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 8-yl)-2-fluorobenzonitrile 194

2-fluoro-4-(2-formyl-6,9- dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 8-yl)benzonitrile 195

8-(4-cyano-3-fluorophenyl)- N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonane- 2-carbothioamide196

methyl 8-(4-cyano-3- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonane- 2-carboxylate197

4-(2-acetyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 8-yl)-2-fluorobenzonitrile 198

8-(4-cyano-3-fluorophenyl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane- 2-carboxamide 199

8-(4-cyano-3-fluorophenyl)- N-cyclopropyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonane- 2-carboxamide200

8-(4-cyano-3-fluorophenyl)- N-(1-methyl-1H-pyrazol-4-yl)-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane- 2-carboxamide 201

8-(4-cyano-3-fluorophenyl)- N,N-dimethyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonane- 2-carboxamide202

4-(2-acetyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 8-yl)-3-fluorobenzonitrile 203

4-(2-(cyclopropanecarbonyl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 8-yl)-3-fluorobenzonitrile 204

8-(4-cyano-2-fluorophenyl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane- 2-carboxamide 205

4-(2-acetyl-6-(4- chlorobenzyl)-7,10-dioxo- 2,6,9-triazaspiro[4.5]decan-9-yl)-3-fluorobenzonitrile 206

(S)-4-(2-acetyl-6-(4- chlorobenzyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]decan- 9-yl)-3-fluorobenzonitrile 207

tert-butyl (S)-6-(4- chlorobenzyl)-9-(4-cyano-2-fluorophenyl)-7,10-dioxo- 2,6,9-triazaspiro[4.5]decane- 2-carboxylate208

tert-butyl (S)-9-(4-cyano-2- fluorophenyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]decane- 2-carboxylate209

(S)-4-(2-acetyl-7,10-dioxo- 6-(4-(trifluoromethyl)-benzyl)-2,6,9-triazaspiro- [4.5]decan-9-yl)-3- fluorobenzonitrile 210

(S)-4-(6-(4-chlorobenzyl)- 2-(oxetane-3-carbonyl)- 7,10-dioxo-2,6,9-triazaspiro[4.5]decan-9-yl)- 3-fluorobenzonitrile 211

methyl (S)-6-(4- chlorobenzyl)-9-(4-cyano- 2-fluorophenyl)-7,10-dioxo-2,6,9-triazaspiro- [4.5]decane-2-carboxylate 212

(S)-4-(6-(4-chlorobenzyl)- 2-(cyclobutanecarbonyl)- 7,10-dioxo-2,6,9-triazaspiro[4.5]decan-9-yl)- 3-fluorobenzonitrile 213

(S)-4-(6-(4-chlorobenzyl)- 2-(cyclopropanecarbonyl)- 7,10-dioxo-2,6,9-triazaspiro[4.5]decan-9-yl)- 3-fluorobenzonitrile 214

(S)-4-(6-(4-chlorobenzyl)- 7,10-dioxo-2-propionyl-2,6,9-triazaspiro[4.5]decan- 9-yl)-3-fluorobenzonitrile 215

(S)-3-fluoro-4-(2-(oxetane- 3-carbonyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]decan-9-yl)benzonitrile 216

methyl (S)-9-(4-cyano-2- fluorophenyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]decane- 2-carboxylate217

(S)-4-(2-(cyclobutane- carbonyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]decan-9-yl)-3-fluorobenzonitrile 218

(S)-4-(7,10-dioxo-2- propionyl-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decan- 9-yl)-3-fluorobenzonitrile 219

(S)-4-(2-(cyclopropane- carbonyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]decan-9-yl)-3-fluorobenzonitrile 220

(S)-4-(6-(4-chlorobenzyl)-2- formyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decan-9-yl)- 3-fluorobenzonitrile 221

(S)-4-(6-(4-chlorobenzyl)- 2-isobutyryl-7,10-dioxo-2,6,9-triazaspiro[4.5]decan- 9-yl)-3-fluorobenzonitrile 222

(S)-3-fluoro-4-(2-formyl- 7,10-dioxo-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decan- 9-yl)benzonitrile 223

(S)-3-fluoro-4-(2-isobutyryl- 7,10-dioxo-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decan- 9-yl)benzonitrile 224

(S)-2-acetyl-6-(4-chloro- benzyl)-9-(4-(difluoro- methoxy)phenyl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 225

(S)-2-acetyl-6-(4-chloro- benzyl)-9-(5-methoxy- pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 226

tert-butyl (2s,4s)-8-(4- cyano-2-fluorophenyl)-6,9-dioxo-5-(4-(trifluoro- methyl)benzyl)-5,8- diazaspiro[3.5]nonane-2-carboxylate 227

tert-butyl (2r,4r)-8-(4- cyano-2-fluorophenyl)- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxylate 228

4-((2s,4s)-2-(1,3,4-oxadiazol- 2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile 229

3-fluoro-4-((2s,4s)-2-(3- methyl-1,2,4-oxadiazol-5- yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile230

3-fluoro-4-((2s,4s)-2-(3-(1- hydroxyethyl)-1,2,4-oxadiazol-5-yl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonan-8- yl)benzonitrile 231

3-fluoro-4-((2s,4s)-2-(5- methyloxazol-2-yl)-6,9-dioxo-5-(4-trifluoromethyl)- benzyl)-5,8-diazaspiro-[3.5]nonan-8-yl]benzonitrile 232

4-((2s,4s)-2-(3-cyclopropyl- 1,2,4-oxadiazol-5-yl)-6,9-dioxo-5-(4-(trifluoro- methyl)benzyl)-5,8- diazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile 233

3-fluoro-4-((2s,4s)-2-(5- methyl-1,3,4-oxadiazol-2- yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile234

3-fluoro-4-((2s,4s)-2-(4- methyloxazol-2-yl)-6,9- dioxo-5-(4-(trifluoro-methyl)benzyl)-5,8- diazaspiro[3.5]nonan- 8-yl)benzonitrile 235

3-fluoro-4-((2s,4s)-2- (morpholine-4-carbonyl)- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile236

4-((2s,4s)-2-(azetidine-1 carbonyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile 237

(2s,4s)-8-(4-cyano-2- fluorophenyl)-N-cyclo- propyl-N-methyl-6,9-dioxo-5-(4-(trifluoro- methyl)benzyl)-5,8- diazaspiro[3.5]nonane-2-carboxamide 238

3-fluoro-4-((2s,4s)-2-(4- hydroxypiperidine-1- carbonyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile239

4-((2s,4s)-2-(5- (difluoromethyl)-1,3,4- oxadiazol-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro- [3.5]nonan-8-yl)-3-fluorobenzonitrile 240

4-((2s,4s)-2-(5- (difluoromethyl)-1,3,4- oxadiazol-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro- [3.5]nonan-8-yl)-3-fluorobenzonitrile 241

4-((2s,4s)-2-(3- (difluoromethyl)-1,2,4- oxadiazol-5-yl)-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro- [3.5]nonan-8-yl)-3-fluorobenzonitrile 242

(2s,4s)-8-(4-cyano-2- fluorophenyl)-N-cydopropyl- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 243

(2s,4S)-8-(4-cyano-2- fluorophenyl)-N-((1s,3S)-3-hydroxycyclobutyl)-6,9- dioxo-5-(4-(trifluoro- methyl)benzyl)-5,8-diazaspiro[3.5]nonane-2- carboxamide 244

(2s,4S)-8-(4-cyano-2- fluorophenyl)-N-((1r,3R)-3-hydroxycyclobutyl)-6,9- dioxo-5-(4-(trifluoro- methyl)benzyl)-5,8-diazaspiro[3.5]nonane-2- carboxamide 245

1-((2s,4s)-8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan-2-yl)-3-methylurea 246

1-((2s,4s)-8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan-2-yl)-3-cyclopropylurea 247

1-((2s,4s)-8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan-2-yl)-3-(oxetan-3-yl)urea 248

(2s,4s)-8-(4-cyano-2- fluorophenyl)-N-(2- hydroxyethyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide249

(2s,4s)-8-(4-cyano-2- fluorophenyl)-N-cyclobutyl- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 250

(2s,4s)-8-(4-cyano-2- fluorophenyl)-N-(3,3- difluorocyclobutyl)-6,9-dioxo-5-(4-(trifluoro- methyl)benzyl)-5,8- diazaspiro[3.5]nonane-2-carboxamide 251

3-fluoro-4-((2s,4s)-2- (hydroxymethyl)-6,9- dioxo-5-(4-(trifluoro-methyl)benzyl)-5,8- diazaspiro[3.5]nonan-8- yl)benzonitrile 252

(2s,4s)-8-(4-cyano-2- fluorophenyl)-N-methyl-N-(oxetan-3-yl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane- 2-carboxamide 253

3-fluoro-4-((2s,4s)-2-(2- hydroxypropan-2-yl)-6,9-dioxo-5-(4-(trifluoro- methyl)benzyl)-5,8- diazaspiro[3.5]nonan-8-yl)benzonitrile 254

(2s,4s)-8-(4-chloro-2- fluorophenyl)-2-(2- hydroxypropan-2-yl)-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 6,9-dione 255

(2s,4s)-8-(4-chloro-2- fluorophenyl)-2-hydroxy- 5-(4-(trifluoromethyl)-benzyl)-5,8-diazaspiro- [3.5]nonane-6,9-dione 256

3-fluoro-4-((2s,4s)-2- hydroxy-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile 257

(2r,4r)-8-(4-chloro-2- fluorophenyl)-2-hydroxy-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 6,9-dione 258

3-fluoro-4-((2r,4r)-2- hydroxy-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile 259

(2r,4r)-8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide260

(2s,4s)-8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide261

(2s,4s)-8-(4-cyano-2- fluorophenyl)-N-methyl- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 262

(2r,4r)-8-(4-cyano-2- fluorophenyl)-N,N- dimethyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 263

(2r,4r)-8-(4-cyano-2- fluorophenyl)-N-methyl- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 264

(2s,4s)-8-(4-cyano-2- fluorophenyl)-N,N- dimethyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 265

methyl (2s,4s)-5-(4- chlorobenzyl)-8-(4-cyano-2-fluorophenyl)-6,9-dioxo- 5,8-diazaspiro[3.5]nonane- 2-carboxylate 266

(2s,4s)-5-(4-chlorobenzyl)- 8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5,8-diazaspiro- [3.5]nonane-2-carboxamide 267

4-((2s,4s)-5-(4-chloro- benzyl)-2-(4-hydroxy- piperidine-1-carbonyl)-6,9-dioxo-5,8-diazaspiro- [3.5]nonan-8-yl)-3 fluorobenzonitrile 268

(2s,4s)-8-(4-chloro-2- fluorophenyl)-5-(4- chlorobenzyl)-2-(4-hydroxypiperidine-1- carbonyl)-5,8-diazaspiro- [3.5]nonane-6,9-dione 269

3-fluoro-4-(3-(hydroxy- methyl)-3-methyl-2,5- dioxo-4-(4-(trifluoro-methyl)benzyl)piperazin- 1-yl)benzonitrile 270

1-(4-chloro-2-fluorophenyl)- 3-(hydroxymethyl)-3-methyl-4-(4-(trifluoro- methyl)benzyl)piperazine- 2,5-dione 271

7-(4-chloro-2-fluorophenyl)- 4-(4-(trifluoromethyl)-benzyl)-4,7-diazaspiro- [2.5]octane-5,8-dione 272

8-(4-chloro-2-fluorophenyl)- 5-(4-(trifluoromethyl)-benzyl)-5,8-diazaspiro- [3.5]nonane-6,9-dione 273

1-(4-chloro-2-fluorophenyl)- 3,3-dimethyl-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 274

8-(4-chloro-2-fluorophenyl)- 5-(4-(trifluoromethyl)- benzyl)-2-oxa-5,8-diazaspiro[3.5]nonane- 6,9-dione 275

(R)-1-(4-chloro-2-fluoro- phenyl)-3-methyl-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 276

(S)-1-(4-chloro-2-fluoro- phenyl)-3-methyl-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 277

1-(4-chloro-2-fluorophenyl)- 4-(4-(trifluoromethyl)-benzyl)piperazine-2,5-dione 278

4-(5,8-dioxo-4-(4- (trifluoromethyl)benzyl)- 4,7-diazaspiro[2.5]octan-7-yl)-3-fluorobenzonitrile 279

4-(3,3-dimethyl-2,5-dioxo- 4-(4-(trifluoromethyl)-benzyl)piperazin-1-yl)-3- fluorobenzonitrile 280

4-(6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2- oxa-5,8-diazaspiro[3.5]-nonan-8-yl)-3- fluorobenzonitrile 281

1-(4-chloro-2-fluorophenyl)- 3-(oxetan-3-yl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 282

3-fluoro-4-(3-(oxetan-3-yl)- 2,5-dioxo-4-(4- (trifluoromethyl)benzyl)-piperazin-1-yl)benzonitrile 283

(S)-3-fluoro-4-(3-isopropyl- 2,5-dioxo-4-(4- (trifluoromethyl)benzyl)-piperazin-1-yl)benzonitrile 284

(S)-4-(3-cyclobutyl-2,5- dioxo-4-(4-(trifluoromethyl)-benzyl)piperazin-1-yl)-3- fluorobenzonitrile 285

(S)-4-(3-(tert-butoxymethyl)- 2,5-dioxo-4-(4-(trifluoro-methyl)benzyl)piperazin-1- yl)-3-fluorobenzonitrile 286

4-(7,10-dioxo-6-(4- (trifluoromethyl)benzyl)-2-oxa-6,9-diazaspiro[4.5]decan- 9-yl)-3-fluorobenzonitrile 287

(S)-3-fluoro-4-(3- (hydroxymethyl)-2,5-dioxo- 4-(4-(trifluoromethyl)-benzyl)piperazin-1-yl)- benzonitrile 288

4-(4-chlorobenzyl)-3-(4- chlorophenyl)-1-isopropyl- piperazine-2,5-dione289

(S)-4-(4-chlorobenzyl)-3- (4-chlorophenyl)-1- isopropylpiperazine-2,5-dione 290

(R)-4-(4-chlorobenzyl)-3- (4-chlorophenyl)-1- isopropylpiperazine-2,5-dione 291

(S)-3-(4-chlorophenyl)-4- ((5-chloropyridin-2-yl)- methyl)-1-isopropyl-piperazine-2,5-dione 292

(R)-3-(4-chlorophenyl)-4- ((5-chloropyridin-2- yl)methyl)-1-isopropyl-piperazine-2,5-dione 293

3-(4-chlorophenyl)-4-((5- chloropyridin-2-yl)methyl)-1-isopropylpiperazine- 2,5-dione 294

4-benzyl-3-(4-chlorophenyl)- 1-isopropylpiperazine-2,5- dione 295

(R)-4-(4-chlorobenzyl)-3- (5-chloropyridin-2-yl)-1- isopropylpiperazine-2,5-dione 296

(S)-4-(4-chlorobenzyl)-3- (5-chloropyridin-2-yl)- 1-isopropylpiperazine-2,5-dione 297

4-(4-chlorobenzyl)-3-(5- chloropyridin-2-yl)-1- isopropylpiperazine-2,5-dione 298

4-(3-chlorobenzyl)-3-(4- chlorophenyl)-1- isopropylpiperazine- 2,5-dione299

3-(4-chlorophenyl)-4-(3- fluorobenzyl)-1- isopropylpiperazine- 2,5-dione300

3-(4-chlorophenyl)-1- isopropyl-4-(2- methylbenzyl)piperazine- 2,5-dione301

2-((2-(4-chlorophenyl)-4- isopropyl-3,6-dioxo- piperazin-1-yl)methyl)-benzonitrile 302

4-(2-chlorobenzyl)-3-(4- chlorophenyl)-1- isopropylpiperazine- 2,5-dione303

3-(4-chlorophenyl)-4-(4- fluorobenzyl)-1- isopropylpiperazine- 2,5-dione304

3-(4-chlorophenyl)-1- isopropyl-4-(3-methyl- benzyl)piperazine-2,5-dione 305

3-(4-chlorophenyl)-1- isopropyl-4-(4- methylbenzyl)piperazine- 2,5-dione306

3-((2-(4-chlorophenyl)-4- isopropyl-3,6-dioxo- piperazin-1-yl)methyl)-benzonitrile 307

4-((2-(4-chlorophenyl)-4- isopropyl-3,6-dioxo- piperazin-1-yl)methyl)-benzonitrile 308

3-(4-chlorophenyl)-1- isopropyl-4-(3-(trifluoro-methyl)benzyl)piperazine- 2,5-dione 309

3-(4-chlorophenyl)-1- isopropyl-4-(4-(trifluoro-methyl)benzyl)piperazine- 2,5-dione 310

4-(4-chlorobenzyl)-3-(2- chlorophenyl)-1- isopropylpiperazine- 2,5-dione311

4-(4-chlorobenzyl)-3-(4- fluorophenyl)-1- isopropylpiperazine- 2,5-dione312

4-(4-chlorobenzyl)-3-(3- chlorophenyl)-1- isopropylpiperazine- 2,5-dione313

4-(4-chlorobenzyl)-1- isopropyl-3-(4-methoxy-phenyl)piperazine-2,5-dione 314

4-(4-chlorobenzyl)-1- isopropyl-3-(4-(trifluoro-methyl)phenyl)piperazine- 2,5-dione 315

3-(4-chlorophenyl)-1- isopropyl-4-((5- (trifluoromethyl)pyridin-2-yl)methyl)piperazine- 2,5-dione 316

4-(4-chlorobenzyl)-3-(4- chlorophenyl)-1-isopropyl-3-methylpiperazine-2,5-dione 317

1′-(4-chlorobenzyl)-4′- isopropyl-1,3- dihydrospiro[indene-2,2′-piperazine]-3′,6′-dione 318

5-(4-chlorobenzyl)-8- isopropyl-2-phenyl-5,8- diazaspiro[3.5]nonane-6,9-dione 319

4′-isopropyl-1′-(4- (trifluoromethyl)benzyl)- 2,3-dihydrospiro[indene-1,2′-piperazine]-3′,6′-dione 320

8-(1-cyanopropan-2-yl)-N- methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-2-carboxamide321

8-((1S,3R)-3-cyano- cyclopentyl)-N-methyl- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-2-carboxamide322

2-acetyl-8-((1r,4r)-4- methylcyclohexyl)-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 323

2-acetyl-8-(4-ethylcyclo- hexyl)-5-(4-(trifluoro- methyl)benzyl)-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 324

2-acetyl-8-(4-(difluoro- methyl)cyclohexyl)-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-6,9-dione325

(1r,4r)-4-(2-acetyl-6,9-dioxo- 5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8- yl)cyclohexane-l-carbonitrile 326

2-acetyl-8-cycloheptyl-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 327

9-isopropyl-2-phenyl-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]- decane-1,7,10-trione 328

(S)-9-imino-8-isopropyl-2- phenyl-5-(1-(4-(trifluoro-methyl)phenyl)ethyl)- 2,5,8-triazaspiro[3.5]nonan- 6-one 329

5-(4-chlorobenzyl)-8- isopropyl-7-methyl-2- phenyl-2,5,8-triazaspiro-[3.5]nonane-6,9-dione 330

6-(4-chlorobenzyl)-9- isopropyl-2-(1-methyl-1H- pyrazol-4-yl)-2,6,9-triazaspiro[4.5]decane- 1,7,10-trione 331

6-(4-chlorobenzyl)-9- isopropyl-2-phenyl-2,6,9- triazaspiro[4.5]decane-3,7,10-trione 332

6-(4-chlorobenzyl)-9- isopropyl-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane- 3,7,10-trione 333

6-(4-chlorobenzyl)-9- isopropyl-2-(2-methyl- pyridin-4-yl)-2,6,9-triazaspiro[4.5]decane- 1,7,10-trione 334

6-(4-chlorobenzyl)-9-(4- methoxybenzyl)-N-methyl- 7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2- carboxamide 335

N-methyl-6,9-dioxo-5,8- bis(4-(trifluoromethyl)- benzyl)-2,5,8-triazaspiro[3.5]nonane- 2-carboxamide 336

8-(4-cyanobenzyl)-N- methyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 337

8-(4-chlorobenzyl)-N-methyl- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 338

8-(1-(4-cyanophenyl)ethyl)- N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-2-carboxamide339

(S)-4-(2-acetyl-6,9-dioxo- 5-(1-(4-(trifluoromethyl)-phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonan- 8-yl)-3-fluorobenzonitrile340

(S)-2-acetyl-8-(4-chloro-2- fluorophenyl)-5-(1-(4-(trifluoromethyl)phenyl)- ethyl)-2,5,8-triazaspiro-[3.5]nonane-6,9-dione 341

2-acetyl-8-(4-chloro-2- fluorophenyl)-7-methyl-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-6,9-dione342

(2r,4r)-8-isopropyl-2-(5- methylthiazol-2-yl)-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 6,9-dione 343

(2s,4s)-8-isopropyl-N- methyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane- 2-carboxamide 344

(2s,4s)-2-(4,5-dimethyl- oxazol-2-yl)-8-isopropyl-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 6,9-dione 345

(2s,4s)-8-isopropyl-2-(4- methyloxazol-2-yl)-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 6,9-dione 346

6-((S)-6-((R)-1-(4- chlorophenyl)-2-hydroxy- ethyl)-9-isopropyl-7,10-dioxo-2,6,9-triazaspiro- [4.5]decan-2-yl)- nicotinonitrile 347

6-(5-(4-chlorobenzyl)-8- isopropyl-7-(methoxy- methyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonan-2- yl)nicotinonitrile 348

6-(6-(4-chlorobenzyl)-9-(4- nitrophenyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]decan- 2-yl)nicotinonitrile 349

6-(4-chlorobenzyl)-N- methyl-9-(4-nitrophenyl)- 7,10-dioxo-2,6,9-triazaspiro[4.5]decane- 2-carboxamide 350

6-(6,9-dioxo-8-phenyl-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 2-yl)nicotinonitrile 351

6-(4-chlorobenzyl)-9- isopropyl-2-(pyrimidin-4- yl)-2,6,9-triazaspiro-[4.5]decane-7,10-dione 352

(R)-6-(4-chlorobenzyl)-9- isopropyl-2-(pyrimidin-4-yl)-2,6,9-triazaspiro- [4.5]decane-7,10-dione 353

6-(4-chlorobenzyl)-9- isopropyl-2-(pyrazin-2-yl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 354

(R)-6-(4-chlorobenzyl)-9- isopropyl-2-(pyrazin-2-yl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 355

6-(4-chlorobenzyl)-9- isopropyl-2-(5-methyl- pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 356

(R)-6-(4-chlorobenzyl)-9- isopropyl-2-(5-methyl- pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 357

6-(4-chlorobenzyl)-2-(5- fluoropyridin-2-yl)-9- isopropyl-2,6,9-triazaspiro[4.5]decane- 7,10-dione 358

(R)-6-(4-chlorobenzyl)-2- (5-fluoropyridin-2-yl)-9- isopropyl-2,6,9-triazaspiro[4.5]decane- 7,10-dione 359

6-(4-chlorobenzyl)-9- isopropyl-2-(pyridazin-3- yl)-2,6,9-triazaspiro-[4.5]decane-7,10-dione 360

(R)-6-(4-chlorobenzyl)-9- isopropyl-2-(pyridazin-3-yl)-2,6,9-triazaspiro- [4.5]decane-7,10-dione 361

6-(4-chlorobenzyl)-9- isopropyl-2-(1-methyl-2- oxo-1,2-dihydropyridin-4-yl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 362

(R)-6-(4-chlorobenzyl)-9- isopropyl-2-(1-methyl-2-oxo-1,2-dihydropyridin-4- yl)-2,6,9-triazaspiro- [4.5]decane-7,10-dione363

6-(4-chlorobenzyl)-9- isopropyl-2-(2-oxo-1,2-dihydropyridin-4-yl)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 364

(R)-6-(4-chlorobenzyl)-9- isopropyl-2-(2-oxo-1,2-dihydropyridin-4-yl)-2,6,9- triazaspiro[4.5]decane-7,10- dione 365

6-(4-chlorobenzyl)-9- isopropyl-2-(1-methyl-1H- pyrazol-4-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 366

(R)-6-(4-chlorobenzyl)-9- isopropyl-2-(1-methyl-1H- pyrazol-4-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 367

6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2- carboxamide 368

(R)-6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2- carboxamide 369

6-(4-chlorobenzyl)-N- cyclopropyl-9-isopropyl- 7,10-dioxo-2,6,9-triazaspiro[4.5]decane- 2-carboxamide 370

(R)-6-(4-chlorobenzyl)-N- cyclopropyl-9-isopropyl- 7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2- carboxamide 371

6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-N- phenyl-2,6,9-triazaspiro-[4.5]decane-2-carboxamide 372

(R)-6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-N-phenyl-2,6,9-triazaspiro- [4.5]decane-2-carboxamide 373

6-(4-chlorobenzyl)-9- isopropyl-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 374

(R)-6-(4-chlorobenzyl)-9- isopropyl-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 375

6-(4-chlorobenzyl)-9- isopropyl-2-phenyl-2,6,9- triazaspiro[4.5]decane-7,10-dione 376

(R)-6-(4-chlorobenzyl)-9- isopropyl-2-phenyl-2,6,9-triazaspiro[4.5]decane- 7,10-dione 377

6-(4-chlorobenzyl)-9- isopropyl-2-(2-methyl- pyridin-4-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 378

(R)-6-(4-chlorobenzyl)-9- isopropyl-2-(2-methyl- pyridin-4-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 379

6-(4-chlorobenzyl)-9- isopropyl-N-methyl-7,10- dioxo-2,6,9-triazaspiro-[4.5]decane-2-carboxamide 380

(R)-6-(4-chlorobenzyl)-9- isopropyl-N-methyl-7,10-dioxo-2,6,9-triazaspiro- [4.5]decane-2-carboxamide 381

6-(4-chlorobenzyl)-N-ethyl- 9-isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]- decane-2-carboxamide 382

(R)-6-(4-chlorobenzyl)-N- ethyl-9-isopropyl-7,10-dioxo-2,6,9-triazaspiro- [4.5]decane-2-carboxamide 383

6-(4-chlorobenzyl)-N,9- diisopropyl-7,10-dioxo- 2,6,9-triazaspiro[4.5]-decane-2-carboxamide 384

(R)-6-(4-chlorobenzyl)- N,9-diisopropyl-7,10- dioxo-2,6,9-triazaspiro-[4.5]decane-2-carboxamide 385

6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-N- (pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane-2- carboxamide 386

(R)-6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo-N- (pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane-2- carboxamide 387

6-(4-chlorobenzyl)-9- isopropyl-N-(2-methoxy- ethyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2- carboxamide 388

(R)-6-(4-chlorobenzyl)-9- isopropyl-N-(2-methoxy-ethyl)-7,10-dioxo-2,6,9- triazaspiro[4.5]decane-2- carboxamide 389

6-((S)-1-(4-chlorophenyl)- ethyl)-9-isopropyl-2- (pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 390

(R)-4-(2-acetyl-6-(4- chlorobenzyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]decan- 9-yl)-3-fluorobenzonitrile 391

tert-butyl 6-(4-chlorobenzyl)- 9-(4-cyano-2-fluorophenyl)-7,10-dioxo-2,6,9- triazaspiro[4.5]decane-2- carboxylate 392

tert-butyl (R)-6-(4-chloro- benzyl)-9-(4-cyano-2-fluorophenyl)-7,10-dioxo- 2,6,9-triazaspiro[4.5]decane- 2-carboxylate393

tert-butyl 9-(4-cyano-2- fluorophenyl)-7,10-dioxo-6-(4-(trifluoromethyl)- benzyl)-2,6,9-triazaspiro-[4.5]decane-2-carboxylate 394

tert-butyl (R)-9-(4-cyano-2- fluorophenyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]decane- 2-carboxylate395

4-(2-acetyl-7,10-dioxo-6- (4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decan- 9-yl)-3-fluorobenzonitrile 396

(R)-4-(2-acetyl-7,10-dioxo-6- (4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decan- 9-yl)-3-fluorobenzonitrile 397

4-(6-(4-chlorobenzyl)-2- (oxetane-3-carbonyl)-7,10-dioxo-2,6,9-triazaspiro- [4.5]decan-9-yl)-3- fluorobenzonitrile 398

(R)-4-(6-(4-chlorobenzyl)- 2-(oxetane-3-carbonyl)- 7,10-dioxo-2,6,9-triazaspiro[4.5]decan-9-yl)- 3-fluorobenzonitrile 399

methyl 6-(4-chlorobenzyl)- 9-(4-cyano-2-fluorophenyl)- 7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2- carboxylate 400

methyl (R)-6-(4-chloro- benzyl)-9-(4-cyano-2- fluorophenyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]- decane-2-carboxylate 401

4-(6-(4-chlorobenzyl)-2- (cyclobutanecarbonyl)- 7,10-dioxo-2,6,9-triazaspiro[4.5]decan-9-yl)- 3-fluorobenzonitrile 402

(R)-4-(6-(4-chlorobenzyl)- 2-(cyclobutanecarbonyl)- 7,10-dioxo-2,6,9-triazaspiro[4.5]decan-9-yl)- 3-fluorobenzonitrile 403

4-(6-(4-chlorobenzyl)-2- (cyclopropanecarbonyl)- 7,10-dioxo-2,6,9-triazaspiro[4.5]decan-9-yl)- 3-fluorobenzonitrile 404

(R)-4-(6-(4-chlorobenzyl)- 2-(cyclopropanecarbonyl)- 7,10-dioxo-2,6,9-triazaspiro[4.5]decan-9-yl)- 3-fluorobenzonitrile 405

4-(6-(4-chlorobenzyl)-7,10- dioxo-2-propionyl-2,6,9-triazaspiro[4.5]decan-9-yl)- 3-fluorobenzonitrile 406

(R)-4-(6-(4-chlorobenzyl)- 7,10-dioxo-2-propionyl-2,6,9-triazaspiro[4.5]decan- 9-yl)-3-fluorobenzonitrile 407

3-fluoro-4-(2-(oxetane-3- carbonyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]decan- 9-yl)benzonitrile408

(R)-3-fluoro-4-(2-(oxetane- 3-carbonyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]decan-9-yl)benzonitrile 409

methyl 9-(4-cyano-2-fluoro- phenyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]- decane-2-carboxylate410

methyl (R)-9-(4-cyano-2- fluorophenyl)-7,10-dioxo-6-(4-(trifluororriethyl)benzyl)- 2,6,9-triazaspiro[4.5]decane-2-carboxylate 411

4-(2-(cyclobutanecarbonyl)- 7,10-dioxo-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decan- 9-yl)-3-fluorobenzonitrile 412

(R)-4-(2-(cyclobutane- carbonyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]decan-9-yl)-3-fluorobenzonitrile 413

4-(7,10-dioxo-2-propionyl- 6-(4-(trifluoromethyl)-benzyl)-2,6,9-triazaspiro- [4.5]decan-9-yl)-3- fluorobenzonitrile 414

(R)-4-(7,10-dioxo-2- propionyl-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decan- 9-yl)-3-fluorobenzonitrile 415

4-(2-(cyclopropanecarbonyl)- 7,10-dioxo-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decan- 9-yl)-3-fluorobenzonitrile 416

(R)-4-(2-(cyclopropane- carbonyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)- 2,6,9-triazaspiro[4.5]decan-9-yl)-3-fluorobenzonitrile 417

4-(6-(4-chlorobenzyl)-2- formyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decan-9-yl)- 3-fluorobenzonitrile 418

(R)-4-(6-(4-chlorobenzyl)- 2-formyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decan-9-yl)- 3-fluorobenzonitrile 419

4-(6-(4-chlorobenzyl)-2- isobutyryl-7,10-dioxo-2,6,9-triazaspiro[4.5]decan- 9-yl)-3-fluorobenzonitrile 420

(R)-4-(6-(4-chlorobenzyl)- 2-isobutyryl-7,10-dioxo-2,6,9-triazaspiro[4.5]decan- 9-yl)-3-fluorobenzonitrile 421

3-fluoro-4-(2-formyl-7,10- dioxo-6-(4-(trifluoro- methyl)benzyl)-2,6,9-triazaspiro[4.5]decan-9- yl)benzonitrile 422

(R)-3-fluoro-4-(2-formyl- 7,10-dioxo-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decan- 9-yl)benzonitrile 423

3-fluoro-4-(2-isobutyryl- 7,10-dioxo-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decan- 9-yl)benzonitrile 424

(R)-3-fluoro-4-(2-isobutyryl- 7,10-dioxo-6-(4- (trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decan- 9-yl)benzonitrile 425

2-acetyl-6-(4-chlorobenzyl)- 9-(4-(difluoromethoxy)-phenyl)-2,6,9-triazaspiro- [4.5]decane-7,10-dione 426

(R)-2-acetyl-6-(4-chloro- benzyl)-9-(4-(difluoro- methoxy)phenyl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 427

2-acetyl-6-(4-chlorobenzyl)- 9-(5-methoxypyridin-2-yl)-2,6,9-triazaspiro[4.5]- decane-7,10-dione 428

(R)-2-acetyl-6-(4-chloro- benzyl)-9-(5-methoxy-pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 429

tert-butyl 8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxylate430

4-(2-(1,3,4-oxadiazol-2-yl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonan- 8-yl)-3-fluorobenzonitrile 431

4-((2r,4r)-2-(1,3,4- oxadiazol-2-yl)-6,9-dioxo- 5-(4-(trifluoromethyl)-benzyl)-5,8-diazaspiro- [3.5]nonan-8-yl)-3- fluorobenzonitrile 432

3-fluoro-4-(2-(3-methyl- 1,2,4-oxadiazol-5-yl)-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro[3.5]-nonan-8-yl)benzonitrile 433

3-fluoro-4-((2r,4r)-2-(3- methyl-1,2,4-oxadiazol-5-yl)- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile434

3-fluoro-4-(2-(3-(1- hydroxyethyl)-1,2,4- oxadiazol-5-yl)-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro[3.5]-nonan-8-yl)benzonitrile 435

3-fluoro-4-((2r,4r)-2-(3-(1- hydroxyethyl)-1,2,4-oxadiazol-5-yl)-6,9-dioxo-5- (4-(trifluoromethyl)-benzyl)-5,8-diazaspiro[3.5]- nonan-8-yl)benzonitrile 436

3-fluoro-4-(2-(5-methyl- oxazol-2-yl)-6,9-dioxo-5-(4-trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile437

3-fluoro-4-((2r,4r)-2-(5- methyloxazol-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro[3.5]-nonan-8-yl)benzonitrile 438

4-(2-(3-cyclopropyl-1,2,4- oxadiazol-5-yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile 439

4-((2r,4r)-2-(3-cyclopropyl- 1,2,4-oxadiazol-5-yl)-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro[3.5]-nonan-8-yl)-3-fluoro- benzonitrile 440

3-fluoro-4-(2-(5-methyl- 1,3,4-oxadiazol-2-yl)-6,9-dioxo-5-(4-(trifluoro- methyl)-benzyl)-5,8- diazaspiro[3.5]nonan-8-yl)benzonitrile 441

3-fluoro-4-((2r,4r)-2-(5- methyl-l,3,4-oxadiazol-2- yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile442

3-fluoro-4-(2-(4- methyloxazol-2-yl)-6,9- dioxo-5-(4-(trifluoro-methyl)benzyl)-5,8- diazaspiro[3.5]nonan-8- yl)benzonitrile 443

3-fluoro-4-((2r,4r)-2-(4- methyloxazol-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro-[3.5]nonan-8-yl)benzonitrile 444

3-fluoro-4-(2-(morpholine-4- carbonyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile445

3-fluoro-4-((2r,4r)-2- (morpholine-4-carbonyl)- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile446

4-(2-(azetidine-1-carbonyl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonan- 8-yl)-3-fluorobenzonitrile 447

4-((2r,4r)-2-(azetidine-1- carbonyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile 448

8-(4-cyano-2-fluorophenyl)- N-cyclopropyl-N-methyl- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 449

(2r,4r)-8-(4-cyano-2- fluorophenyl)-N-cyclo- propyl-N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro-[3.5]nonane-2-carboxamide 450

3-fluoro-4-(2-(4-hydroxy- piperidine-1-carbonyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan-8-yl)benzonitrile 451

3-fluoro-4-((2r,4r)-2-(4- hydroxypiperidine-1- carbonyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile452

8-(4-cyano-2-fluorophenyl)- N-(oxetan-3-yl)-6,9- dioxo-5-(4-(trifluoro-methyl)benzyl)-5,8- diazaspiro[3.5]nonane-2- carboxamide 453

(2r,4r)-8-(4-cyano-2- fluorophenyl)-N-(oxetan-3- yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 454

4-(2-(5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro[3.5]-nonan-8-yl)-3-fluoro- benzonitrile 455

4-((2r,4r)-2-(5- (difluoromethyl)-1,3,4- oxadiazol-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile 456

4-(2-(3-(difluoromethyl)- 1,2,4-oxadiazol-5-yl)-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro-[3.5]nonan-8-yl)-3- fluorobenzonitrile 457

4-((2r,4r)-2-(3- (difluoromethyl)-1,2,4- oxadiazol-5-yl)-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro- [3.5]nonan-8-yl)-3-fluorobenzonitrile 458

8-(4-cyano-2-fluorophenyl)- N-cyclopropyl-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro[3.5]- nonane-2-carboxamide459

(2r,4r)-8-(4-cyano-2-fluoro- phenyl)-N-cyclopropyl- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 460

(2r,4R)-8-(4-cyano-2- fluorophenyl)-N-((1s,3S)- 3-hydroxycyclobutyl)-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane-2-carboxamide 461

(2r,4R)-8-(4-cyano-2- fluorophenyl)-N-((1r,3R)-3-hydroxycyclobutyl)-6,9- dioxo-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane- 2-carboxamide 462

8-(4-cyano-2-fluorophenyl)- N-(3-hydroxycyclobutyl)- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 463

1-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonan-2- yl)-3-methylurea 464

1-((2r,4r)-8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan-2-yl)-3-methylurea 465

1-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonan- 2-yl)-3-cyclopropylurea 466

1-((2r,4r)-8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan-2-yl)-3-cydopropylurea 467

1-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonan-2- yl)-3-(oxetan-3-yl)urea 468

1-((2r,4r)-8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan-2-yl)-3-(oxetan-3-yl)urea 469

8-(4-cyano-2-fluorophenyl)- N-(2-hydroxyethyl)-6,9- dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 470

(2r,4r)-8-(4-cyano-2- fluorophenyl)-N-(2- hydroxyethyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide471

8-(4-cyano-2-fluorophenyl)- N-cyclobutyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide472

(2r,4r)-8-(4-cyano-2- fluorophenyl)-N-cyclobutyl- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 473

8-(4-cyano-2-fluorophenyl)- N-(3,3-difluorocyclobutyl)- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 474

(2r,4r)-8-(4-cyano-2- fluorophenyl)-N-(3,3- difluorocyclobutyl)-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane-2-carboxamide 475

3-fluoro-4-(2- (hydroxymethyl)-6,9- dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile476

3-fluoro-4-((2r,4r)-2- (hydroxymethyl)-6,9- dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile477

8-(4-cyano-2-fluorophenyl)- N-methyl-N-(oxetan-3-yl)- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 478

(2r,4r)-8-(4-cyano-2- fluorophenyl)-N-methyl-N-(oxetan-3-yl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane- 2-carboxamide 479

3-fluoro-4-(2-(2- hydroxypropan-2-yl)-6,9- dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile480

3-fluoro-4-((2r,4r)-2-(2- hydroxypropan-2-yl)-6,9- dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile481

8-(4-chloro-2-fluorophenyl)- 2-(2-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro- [3.5]nonane-6,9-dione482

(2r,4r)-8-(4-chloro-2- fluorophenyl)-2-(2- hydroxypropan-2-yl)-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 6,9-dione 483

8-(4-chloro-2-fluorophenyl)- 2-hydroxy-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane- 6,9-dione 484

3-fluoro-4-(2-hydroxy-6;9- dioxo-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonan- 8-yl)benzonitrile 485

8-(4-cyano-2-fluorophenyl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane- 2-carboxamide 486

8-(4-cyano-2-fluorophenyl)- N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 487

8-(4-cyano-2-fluorophenyl)- N,N-dimethyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide488

methyl 5-(4-chlorobenzyl)- 8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5,8-diazaspiro- [3.5]nonane-2-carboxylate 489

methyl (2r,4r)-5-(4- chlorobenzyl)-8-(4-cyano-2-fluorophenyl)-6,9-dioxo- 5,8-diazaspiro[3.5]nonane- 2-carboxylate 490

5-(4-chlorobenzyl)-8-(4- cyano-2-fluorophenyl)-6,9-dioxo-5,8-diazaspiro- [3.5]nonane-2-carboxamide 491

(2r,4r)-5-(4-chlorobenzyl)- 8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5,8-diazaspiro- [3.5]nonane-2-carboxamide 492

4-(5-(4-chlorobenzyl)-2-(4- hydroxypiperidine-1-carbonyl)-6,9-dioxo-5,8- diazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile 493

4-((2r,4r)-5-(4-chloro- benzyl)-2-(4-hydroxy- piperidine-1-carbonyl)-6,9-dioxo-5,8- diazaspiro[3.5]nonan-8-yl)- 3-fluorobenzonitrile 494

8-(4-chloro-2-fluoro- phenyl)-5-(4-chlorobenzyl)-2-(4-hydroxypiperidine- 1-carbonyl)-5,8- diazaspiro[3.5]nonane-6,9-dione 495

(2r,4r)-8-(4-chloro-2- fluorophenyl)-5-(4- chlorobenzyl)-2-(4-hydroxypiperidine-1- carbonyl)-5,8-diazaspiro- [3.5]nonane-6,9-dione 496

8-isopropyl-2-(5- methylthiazol-2-yl)-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane- 6,9-dione 497

(2s,4s)-8-isopropyl-2-(5- methylthiazol-2-yl)-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 6,9-dione 498

8-isopropyl-N-methyl-6,9- dioxo-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane- 2-carboxamide 499

(2r,4r)-8-isopropyl-N-methyl- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane- 2-carboxamide 500

2-(4,5-dimethyloxazol-2- yl)-8-isopropyl-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane- 6,9-dione 501

(2r,4r)-2-(4,5-dimethyl- oxazol-2-yl)-8-isopropyl-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 6,9-dione 502

8-isopropyl-2-(4- methyloxazol-2-yl)-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane- 6,9-dione 503

(2r,4r)-8-isopropyl-2-(4- methyloxazol-2-yl)-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 6,9-dione 504

6-(6-(1-(4-chlorophenyl)-2- hydroxyethyl)-9-isopropyl- 7,10-dioxo-2,6,9-triazaspiro[4.5]decan-2- yl)nicotinonitrile 505

6-((R)-6-((R)-1-(4- chlorophenyl)-2- hydroxyethyl)-9-isopropyl-7,10-dioxo-2,6,9- triazaspiro[4.5]decan-2- yl)nicotinonitrile 506

6-(4-chlorobenzyl)-2- (pyridin-2-yl)-9-(tetrahydro- furan-3-yl)-2,6,9-triazaspiro[4.5]decane- 7,10-dione 507

1-(4-chloro-2-fluorophenyl)- 3-methyl-4-(4- (trifluoromethyl)benzyl)-piperazine-2,5-dione 508

3-fluoro-4-(3-isopropyl- 2,5-dioxo-4-(4- (trifluoromethyl)benzyl)-piperazin-1-yl)benzonitrile 509

(R)-3-fluoro-4-(3-isopropyl- 2,5-dioxo-4-(4- (trifluoromethyl)benzyl)-piperazin-1-yl)benzonitrile 510

4-(3-cyclobutyl-2,5-dioxo- 4-(4-(trifluoromethyl)-benzyl)piperazin-1-yl)-3- fluorobenzonitrile 511

(R)-4-(3-cyclobutyl-2,5- dioxo-4-(4-(trifluoro- methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile 512

4-(3-(tert-butoxymethyl)- 2,5-dioxo-4-(4-(trifluoro-methyl)benzyl)piperazin-1- yl)-3-fluorobenzonitrile 513

(R)-4-(3-(tert-butoxy- methyl)-2,5-dioxo-4-(4- (trifluoromethyl)benzyl)-piperazin-1-yl)-3- fluorobenzonitrile 514

3-fluoro-4-(3-(hydroxy- methyl)-2,5-dioxo-4- (4-(trifluoromethyl)-benzyl)piperazin-1-yl)- benzonitrile 515

(R)-3-fluoro-4-(3- (hydroxymethyl)-2,5-dioxo- 4-(4-(trifluoromethyl)-benzyl)piperazin-1-yl)- benzonitrile 516

2-acetyl-8-(4- methylcyclohexyl)-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 517

2-acetyl-8-((ls,4s)-4- methylcyclohexyl)-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonane-6,9-dione 518

8-(3-cyanocydopentyl)- N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-2-carboxamide519

8-((1R,3R)-3-cyano- cyclopentyl)-N-methyl- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-2-carboxamide520

4-(2-acetyl-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]- nonan-8-yl)cyclohexane- 1-carbonitrile 521

(1s,4s)-4-(2-acetyl-6,9- dioxo-5-(4-(trifluoromethyl)-benzyl)-2,5,8-triazaspiro- [3.5]nonan-8-yl)cyclo- hexane-1-carbonitrile522

9-imino-8-isopropyl-2- phenyl-5-(1-(4- (trifluoromethyl)phenyl)-ethyl)-2,5,8-triazaspiro- [3.5]nonan-6-one 523

(R)-9-imino-8-isopropyl- 2-phenyl-5-(1-(4- (trifluoromethyl)phenyl)-ethyl)-2,5,8-triazaspiro- [3.5]nonan-6-one 524

4-(2-acetyl-6,9-dioxo-5-(1- (4-(trifluoromethyl)phenyl)-ethyl)-2,5,8-triazaspiro[3.5]- nonan-8-yl)-3-fluoro- benzonitrile 525

(R)-4-(2-acetyl-6,9-dioxo- 5-(1-(4-(trifluoromethyl)-phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonan-8-yl)- 3-fluorobenzonitrile526

2-acetyl-8-(4-chloro-2- fluorophenyl)-5-(1-(4- (trifluoromethyl)phenyl)-ethyl)-2,5,8-triazaspiro- [3.5]nonane-6,9-dione 527

(R)-2-acetyl-8-(4-chloro-2- fluorophenyl)-5-(1-(4-(trifluoromethyl)phenyl)- ethyl)-2,5,8-triazaspiro-[3.5]nonane-6,9-dione 528

2-acetyl-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]- nonane-6,9-dione 529

6-(2-acetyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 8-yl)-5-methylnicotinonitrile 530

6-(2-acetyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 8-yl)-5-fluoronicotinonitrile 531

3-fluoro-4-(2-(2- (methylamino)benzoyl)- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonan- 8-yl)benzonitrile532

methyl 2-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonan- 2-yl)benzoate533

methyl 3-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonan- 2-yl)benzoate534

methyl 4-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonan- 2-yl)benzoate535

3-fluoro-4-(2-(2-(methyl- amino)phenyl)-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-2,5,8-triazaspiro-[3.5]nonan-8-yl)benzonitrile 536

3-fluoro-4-(2-(3-(methyl- amino)phenyl)-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-2,5,8-triazaspiro-[3.5]nonan-8-yl)benzonitrile 537

2-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 2-yl)-N-methylbenzamide 538

3-fluoro-4-(2-(4- (methylamino)phenyl)- 6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonan- 8-yl)benzonitrile539

3-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 2-yl)-N-methylbenzamide 540

4-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 2-yl)-N-methylbenzamide 541

methyl 4-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonan-2-yl)-2-(methylamino)- benzoate 542

4-(8-(4-cyano-2-fluoro- phenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonan- 2-yl)-N-methyl-2-(methylamino)benzamide 543

methyl 5-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonan-2-yl)-2-(methylamino)- benzoate 544

methyl 2-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonan-2-yl)-6-(methylamino)- benzoate 545

5-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 2-yl)-N-methyl-2- (methylamino)benzamide546

methyl 3-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonan-2-yl)-2-(methylamino)- benzoate 547

3-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan- 2-yl)-N-methyl-2- (methylamino)benzamide548

8-(5-chloro-3-fluoropyridin- 2-yl)-5-(4-(trifluoromethyl)-benzyl)-5,8-diazaspiro- [3.5]nonane-6,9-dione 549

1-(5-chloro-3-fluoropyridin- 2-yl)-3,3-dimethyl-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 550

7-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-(trifluoromethyl)-benzyl)-4,7-diazaspiro- [2.5]octane-5,8-dione 551

8-(5-chloro-3-fluoropyridin- 2-yl)-5-(4-(trifluoromethyl)-benzyl)-2-oxa-5,8- diazaspiro[3.5]nonane- 6,9-dione 552

8-(5-chloro-3-fluoropyridin- 2-yl)-N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-2,5,8-triazaspiro-[3.5]nonane-2-carboxamide 553

9-(5-chloro-3-fluoropyridin- 2-yl)-6-(4-(trifluoromethyl)-benzyl)-2-oxa-6,9- diazaspiro[4.5]decane- 7,10-dione 554

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-isopropyl-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 555

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-cyclobutyl-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 556

(S)-2-acetyl-8-(5-chloro-3- fluoropyridin-2-yl)-5-(1-(4-chlorophenyl)ethyl)-2,5,8- triazaspiro[3.5]nonane-6,9- dione 557

(2r,4r)-8-(5-chloro-3-fluoro- pyridin-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide558

(S)-8-(5-chloro-3-fluoro- pyridin-2-yl)-5-(2-(4-chlorophenyl)ethyl)-2-oxa- 5,8-diazaspiro[3.5]nonane- 6,9-dione 559

(S)-8-(5-chloro-3-fluoro- pyridin-2-yl)-5-(1-(4- chlorophenyl)ethyl)-N-cyclopropyl-6,9-dioxo- 2,5,8-triazaspiro[3.5]- nonane-2-carboxamide 560

(S)-8-(5-chloro-3-fluoro- pyridin-2-yl)-5-(1-(4- chlorophenyl)ethyl)-N-ethyl-6,9-dioxo-2,5,8- triazaspiro[3.5]nonane-2- carboxamide 561

(S)-8-(5-chloro-3-fluoro- pyridin-2-yl)-5-(1-(4- chlorophenyl)ethyl)-N-isopropyl-6,9-dioxo-2,5,8- triazaspiro[3.5]nonane-2- carboxamide 562

(S)-8-(5-chloro-3-fluoro- pyridin-2-yl)-5-(1-(4-chlorophenyl)ethyl)-6,9- dioxo-N-(tetrahydro-2H- pyran-4-yl)-2,5,8-triazaspiro[3.5]nonane-2- carboxamide 563

(S)-8-(5-chloro-3-fluoro- pyridin-2-yl)-5-(1-(4- chlorophenyl)ethyl)-N-methyl-6,9-dioxo-2,5,8- triazaspiro[3.5]nonane-2- carboxamide 564

(S)-2-acetyl-5-(1-(4- chlorophenyl)ethyl)-8-(5- (difluoromethyl)-3-fluoropyridin-2-yl)-2,5,8- triazaspiro[3.5]nonane-6,9- dione 565

(S)-2-acetyl-5-(1-(4- chlorophenyl)ethyl)-8-(3-fluoro-5-(trifluoromethyl)- pyridin-2-yl)-2,5,8- triazaspiro[3.5]nonane-6,9-dione 566

(S)-8-(5-chloro-3-fluoro- pyridin-2-yl)-5-(1-(4- chlorophenyl)ethyl)-2-(2,2-difluoroethyl)-2,5,8- triazaspiro[3.5]nonane- 6,9-dione 567

methyl (S)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(1-(4-chlorophenyl)ethyl)-6,9- dioxo-2,5,8-triazaspiro-[3.5]nonane-2-carboxylate 568

(S)-8-(5-chloro-3-fluoro- pyridin-2-yl)-5-(1-(4-chlorophenyl)ethyl)-6,9- dioxo-2,5,8-triazaspiro-[3.5]nonane-2-carbaldehyde 569

2,2-difluoroethyl (S)-8-(5- chloro-3-fluoropyridin-2-yl)-5-(1-(4-chlorophenyl)- ethyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2- carboxylate 570

(S)-2-acetyl-8-(5-chloro-3- fluoropyridin-2-yl)-5-(1-(4-(trifluoromethyl)phenyl)- ethyl)-2,5,8-triazaspiro-[3.5]nonane-6,9-dione 571

(S)-2-acetyl-8-(5-bromo-3- fluoropyridin-2-yl)-5-(1-(4-(trifluoromethyl)phenyl)- ethyl)-2,5,8-triazaspiro-[3.5]nonane-6,9-dione 572

9-acetyl-4-(5-chloro-3- fluoropyridin-2-yl)-1-(4-(trifluoromethyl)benzyl)- 1,4,9-triazaspiro[5.5]- undecane-2,5-dione 573

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(hydroxymethyl)-3-methyl-4-(4-(trifluoro- methyl)benzyl)piperazine- 2,5-dione 574

8-(5-chloro-3-fluoropyridin- 2-yl)-2-fluoro-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 6,9-dione 575

8-(5-chloro-3-fluoropyridin- 2-yl)-5-(4-chlorobenzyl)-2-oxa-5,8-diazaspiro[3.5]- nonane-6,9-dione 576

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-chlorobenzyl)-3,3-dimethylpiperazine- 2,5-dione 577

7-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-chlorobenzyl)-4,7-diazaspiro[2.5]octane- 5,8-dione 578

(S)-1-(5-chloro-3- fluoropyridin-2-yl)-3-((S)- 1-hydroxyethyl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 579

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-((R)-1- hydroxyethyl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 580

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-((S)-1- hydroxyethyl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 581

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-((R)-1- hydroxyethyl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 582

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3- (hydroxymethyl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 583

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3- (hydroxymethyl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 584

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4- chlorobenzyl)-3-(hydroxymethyl)piperazine- 2,5-dione 585

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-chloro- benzyl)-3-(hydroxy-methyl)piperazine-2,5-dione 586

(S)-1-(5-chloro-3- fluoropyridin-2-yl)-4-(4- chlorobenzyl)-3-isopropylpiperazine- 2,5-dione 587

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4- chlorobenzyl)-3-isopropylpiperazine- 2,5-dione 588

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(hydroxy- methyl)-3-methyl-4-(4-(trifluoromethyl)- benzyl)piperazine- 2,5-dione 589

(R)-l-(5-chloro-3-fluoro- pyridin-2-yl)-3-(hydroxy- methyl)-3-methyl-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 590

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-isopropyl-4-((S)-1-(4-(trifluoro- methyl)phenyl)ethyl) piperazine-2,5-dione 591

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-isopropyl-4-((S)-1-(4-(trifluoro- methyl)phenyl)ethyl) piperazine-2,5-dione 592

(S)-8-(5-chloro-3-fluoro- pyridin-2-yl)-N-methyl- 6,9-dioxo-5-(1-(4-(trifluoromethyl)phenyl)- ethyl)-2,5,8-triazaspiro-[3.5]nonane-2-carboxamide 593

(S)-8-(5-chloro-3-fluoro- pyridin-2-yl)-2-(2,2- difluoroethyl)-5-(l-(4-(trifluoromethyl)phenyl)- ethyl)-2,5,8-triazaspiro-[3.5]nonane-6,9-dione 594

ethyl (2r,4r)-8-(5-chloro-3- fluoropyridin-2-yl)-6,9-dioxo-5-(4-(trifluoro- methyl)benzyl)-5,8- diazaspiro[3.5]nonane-2-carboxylate 595

ethyl (2s,4s)-8-(5-chloro-3- fluoropyridin-2-yl)-6,9-dioxo-5-(4-(trifluoro- methyl)benzyl)-5,8- diazaspiro[3.5]nonane-2-carboxylate 596

ethyl (2r,4r)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4-chlorobenzyl)-6,9-dioxo- 5,8-diazaspiro[3.5]nonane- 2-carboxylate 597

ethyl (2s,4s)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4-chlorobenzyl)-6,9-dioxo- 5,8-diazaspiro[3.5]nonane- 2-carboxylate 598

(2r,4r)-8-(5-chloro-3-fluoro- pyridin-2-yl)-5-(4-chloro-benzyl)-6,9-dioxo-5,8- diazaspiro[3.5]nonane-2- carboxamide 599

(2r,4r)-8-(5-chloro-3- fluoropyridin-2-yl)-N- methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 600

(2r,4r)-8-(5-chloro-3- fluoropyridin-2-yl)-N,N- dimethyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 601

(2s,4s)-8-(5-chloro-3-fluoro- pyridin-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide602

(2s,4s)-8-(5-chloro-3-fluoro- pyridin-2-yl)-N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)- benzyl)-5,8-diazaspiro[3.5]-nonane-2-carboxamide 603

(2s,4s)-8-(5-chloro-3- fluoropyridin-2-yl)-N,N- dimethyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 604

(2s,4s)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4-chlorobenzyl)-6,9-dioxo- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 605

(2s,4s)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4- chlorobenzyl)-N-methyl-6,9-dioxo-5,8- diazaspiro[3.5]nonane- 2-carboxamide 606

(2s,4s)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4-chlorobenzyl)-N,N-dimethyl- 6,9-dioxo-5,8- diazaspiro[3.5]nonane-2-carboxamide 607

(2r,4r)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4- chlorobenzyl)-N-methyl-6,9-dioxo-5,8- diazaspiro[3.5]nonane- 2-carboxamide 608

(2r,4r)-8-(5-chloro-3-fluoro- pyridin-2-yl)-5-(4-chloro-benzyl)-N,N-dimethyl-6,9- dioxo-5,8-diazaspiro[3.5]-nonane-2-carboxamide 609

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoro- methyl)benzyl)piperazine- 2,5-dione 610

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(2-(methylthio)-ethyl)-4-(4-(trifluoro- methyl)-benzyl)piperazine- 2,5-dione 611

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 612

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(2-(methylsulfonyl)-ethyl)-4-(4-(trifluoro- methyl)benzyl)piperazine- 2,5-dione 613

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(2-(methyl-sulfonyl)ethyl)-4-(4- (trifluoromethyl)benzyl)- piperazine-2,5-dione 614

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(2- (methylsulfonyl)ethyl)-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 615

methyl (S)-8-(5-chloro-3- fluoropyridin-2-yl)-6,9-dioxo-5-(1-(4-(trifluoro- methyl)phenyl)ethyl)- 2,5,8-triazaspiro[3.5]-nonane-2-carboxylate 616

(R)-7-(5-chloro-3-fluoro- pyridin-2-yl)-4-(1-(4-chlorophenyl)ethyl)-4,7- diazaspiro[2.5]octane-5,8- dione 617

(2r,4r)-8-(5-chloro-3-methyl- pyridin-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide618

(2r,4r)-8-(5-chloropyridin- 2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 619

(R)-2-acetyl-8-(5-chloro-3- fluoropyridin-2-yl)-5-(1-(4-chlorophenyl)-2-hydroxy- ethyl)-2,5,8-triazaspiro- [3.5]nonane-6,9-dione620

(S)-8-(5-chloro-3-fluoro- pyridin-2-yl)-6,9-dioxo-5-(1-(4-(trifluoromethyl)- phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonane-2-carbaldehyde 621

(3S,6S)-1-(5-chloro-3- fluoropyridin-2-yl)-3- (hydroxymethyl)-6-methyl-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 622

(3R,6R)-1-(5-chloro-3- fluoropyridin-2-yl)-3- (hydroxymethyl)-6-methyl-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 623

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(3-methyloxetan-3-yl)-4-(4-(trifluoro- methyl)-benzyl)piperazine- 2,5-dione 624

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-chlorobenzyl)-3-(3-methyloxetan-3-yl)- piperazine-2,5-dione 625

(S)-N-((4-(5-chloro-3- fluoropyridin-2-yl)-3,6- dioxo-1-(4-(trifluoro-methyl)benzyl)piperazin- 2-yl)methyl)acetamide 626

(R)-N-((4-(5-chloro-3- fluoropyridin-2-yl)-3,6- dioxo-1-(4-(trifluoro-methyl)benzyl)piperazin- 2-yl)methyl)acetamide 627

(S)-N-((4-(5-chloro-3- fluoropyridin-2-yl)-2- methyl-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)- piperazin-2-yl)methyl)- acetamide 628

(R)-N-((4-(5-chloro-3- fluoropyridin-2-yl)-2- methyl-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)- piperazin-2-yl)methyl)- acetamide 629

N-((4-(5-chloro-3-fluoro- pyridin-2-yl)-3,6-dioxo-1-(4-(trifluoromethyl)- benzyl)piperazin-2-yl)- methyl)acetamide 630

N-((4-(5-chloro-3-fluoro- pyridin-2-yl)-2-methyl- 3,6-dioxo-1-(4-(trifluoromethyl)benzyl)- piperazin-2-yl)- methyl)acetamide 631

N-((4-(5-chloro-3-fluoro- pyridin-2-yl)-1-(4-chloro-benzyl)-2-methyl-3,6- dioxopiperazin-2-yl)- methyl)acetamide 632

N-((4-(5-chloro-3-fluoro- pyridin-2-yl)-1-(4-chloro-benzyl)-3,6-dioxopiperazin- 2-yl)methyl)acetamide 633

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-chlorobenzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 634

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-chloro-benzyl)-3-(oxetan-3-yl)- piperazine-2,5-dione 635

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-chloro-benzyl)-3-(oxetan-3-yl)- piperazine-2,5-dione 636

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-chlorobenzyl)-3-(difluoromethyl)-3- methylpiperazine- 2,5-dione 637

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-chloro-benzyl)-3-(difluoromethyl)- 3-methylpiperazine- 2,5-dione 638

(R)-1-(5-chloro-3- fluoropyridin-2-yl)-4-(4- chlorobenzyl)-3-(difluoromethyl)-3- methylpiperazine- 2,5-dione 639

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(oxetan-3-ylmethyl)-4-(4-(trifluoromethyl)- benzyl)piperazine- 2,5-dione 640

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-chlorobenzyl)-3-(oxetan-3-ylmethyl)- piperazine-2,5-dione 641

3-(4-(5-chloro-3-fluoro- pyridin-2-yl)-3,6-dioxo-1-(4-(trifluoromethyl)- benzyl)piperazin-2-yl)-N- methylazetidine-1-carboxamide 642

3-(4-(5-chloro-3-fluoro- pyridin-2-yl)-1-(4-chloro-benzyl)-3,6-dioxopiperin- 2-yl)-N-methylazetidine-1- carboxamide 643

3-(1-acetylazetidin-3-yl)-1- (5-chloro-3-fluoropyridin-2-yl)-4-(4-(trifluoro- methyl)benzyl)piperazine- 2,5-dione 644

3-(1-acetylazetidin-3-yl)- 1-(5-chloro-3-fluoropyridin-2-yl)-4-(4-chlorobenzyl)- piperazine-2,5-dione 645

1-(5-chloro-3-methylpyridin- 2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 646

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-fluorobenzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 647

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(3,4-difluorobenzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 648

4-(4-chloro-3-fluorobenzyl)- 1-(5-chloro-3-fluoropyridin-2-yl)-3-(oxetan-3-yl)- piperazine-2,5-dione 649

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(3-fluoro-4-(trifluoromethyl)benzyl)- 3-(oxetan-3-yl)piperazine- 2,5-dione 650

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-(difluoro-methyl)benzyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 651

1-(5-chloro-3-methylpyridin- 2-yl)-3-(oxetan-3-ylmethyl)-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 652

1-(5-chloro-3-methylpyridin- 2-yl)-3-(3-methyloxetan-3-yl)-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 653

3-(1-acetylazetidin-3-yl)-1- (5-chloro-3-methylpyridin-2-yl)-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 654

1-(5-chloro-3-methylpyridin- 2-yl)-4-(4-chlorobenzyl)-3-(oxetan-3-yl)piperazine-2,5- dione 655

1-(5-chloro-3-methylpyridin- 2-yl)-4-(4-chlorobenzyl)-3-(oxetan-3-ylmethyl)- piperazine-2,5-dione 656

3-(4-(5-chloro-3-fluoro- pyridin-2-yl)-2-methyl-3,6-dioxo-1-(4-(trifluoro- methyl)benzyl)piperazin- 2-yl)propanamide 657

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(difluoromethyl)-3-methyl-4-(4-(trifluoro- methyl)-benzyl)piperazine- 2,5-dione 658

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(difluoro-methyl)-3-methyl-4-(4- (trifluoromethyl)benzyl)- piperazine-2,5-dione659

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(difluoro- methyl)-3-methyl-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 660

(S)-1-(5-chloro-3- methylpyridin-2-yl)-4-(4- chlorobenzyl)-3-isopropyl-piperazine-2,5-dione 661

3-((1-acetylazetidin-3- yl)methyl)-1-(5-chloro-3-fluoropyridin-2-yl)-4-(4- (trifluoromethyl)benzyl)- piperazine-2,5-dione662

3-((1-acetylazetidin-3- yl)methyl)-l-(5-chloro-3-fluoropyridin-2-yl)-4-(4- chlorobenzyl)piperazine- 2,5-dione 663

1-(5-chloro-3-methylpyridin- 2-yl)-4-(4-chlorobenzyl)-3-(3-methyloxetan-3-yl)- piperazine-2,5-dione 664

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(3-fluoro-4-methylbenzyl)-3-(oxetan-3- yl)piperazine-2,5-dione 665

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-ethylbenzyl)-3-(oxetan-3-yl)piperazine-2,5- dione 666

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-methylbenzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 667

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-fluoro-3-methyl-benzyl)-3-(oxetan-3-yl)- piperazine-2,5-dione 668

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(3-chloro-4-fluorobenzyl)-3-(oxetan-3- yl)piperazine-2,5-dione 669

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4- (difluoromethyl)benzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 670

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4- (difluoromethyl)benzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 671

(S)-1-(5-chloro-3- methylpyridin-2-yl)-4-(4- chlorobenzyl)-3-(oxetan-3-yl)piperazine-2,5-dione 672

(R)-1-(5-chloro-3- methylpyridin-2-yl)-4-(4- chlorobenzyl)-3-(oxetan-3-yl)piperazine-2,5-dione 673

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(oxetan- 3-ylmethyl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 674

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(oxetan- 3-ylmethyl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 675

(S)-1-(5-chloro-3- fluoropyridin-2-yl)-4-(4- chlorobenzyl)-3-(oxetan-3-ylmethyl)piperazine- 2,5-dione 676

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-chloro-benzyl)-3-(oxetan-3-yl)- methyl)piperazine-2,5-dione 677

(S)-3-(1-acetylazetidin-3- yl)-1-(5-chloro-3- fluoropyridin-2-yl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 678

(S)-3-(1-acetylazetidin-3- yl)-1-(5-chloro-3- fluoropyridin-2-yl)-4-(4-chlorobenzyl)piperazine- 2,5-dione 679

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(3-fluoro-4-(trifluoromethyl)benzyl)- 3-(oxetan-3-yl)piperazine- 2,5-dione 680

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(3-fluoro-4-(trifluoromethyl)benzyl)- 3-(oxetan-3-yl)piperazine- 2,5-dione 681

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(3,4-difluorobenzyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 682

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(3,4-difluorobenzyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 683

(S)-1-(5-chloro-3- fluoropyridin-2-yl)-4-(4- fluorobenzyl)-3-(oxetan-3-yl)piperazine-2,5-dione 684

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4- fluorobenzyl)-3-(oxetan-3-yl)piperazine-2,5-dione 685

(S)-4-(4-chloro-3-fluoro- benzyl)-l-(5-chloro-3- fluoropyridin-2-yl)-3-(oxetan-3-yl)piperazine- 2,5-dione 686

(R)-4-(4-chloro-3-fluoro- benzyl)-1-(5-chloro-3- fluoropyridin-2-yl)-3-(oxetan-3-yl)piperazine- 2,5-dione 687

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(tetrahydro-2H-thiopyran-4-yl)-4-(4- (trifluoromethyl)benzyl)- piperazine-2,5-dione 688

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(tetrahydro-2H-pyran-4-yl)-4-(4-(trifluoro- methyl)benzyl)piperazine- 2,5-dione 689

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(1,1-dioxidotetra-hydro-2H-thiopyran-4-yl)- 4-(4-(trifluoromethyl)-benzyl)piperazine-2,5-dione 690

(S)-1-(5-chloro-3-methyl- pyridin-2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 691

1-(3-fluoro-5-methylpyridin- 2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 692

(S)-1-(3-fluoro-5-methyl- pyridin-2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 693

(R)-1-(3-fluoro-5-methyl- pyridin-2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 694

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(3-fluoro-4-methylbenzyl-3-(oxetan- 3-yl)piperazine-2,5-dione 695

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(3-fluoro- 4-methylbenzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 696

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-fluoro- 3-methylbenzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 697

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-fluoro-3-methylbenzyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 698

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(3-chloro-4-fluorobenzyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 699

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(3-chloro-4-fluorobenzyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 700

1-(4-bromo-2-fluoro- phenyl)-4-(4-fluorobenzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 701

2-acetyl-8-(2-fluoro-4- (1,2,4-oxadiazol-3-yl)- phenyl)-5-(4-(trifluoro-methyl)benzyl)-2,5,8- triazaspiro[3.5)nonane- 6,9-dione 702

2-acetyl-8-(2-fluoro-4-(5- methyl-1,2,4-oxadiazol-3-yl)phenyl)-5-(4-(trifluoro- methyl)benzyl)-2,5,8-triazaspiro[3.51nonane- 6,9-dione 703

1-(3-fluoro-5-methoxy- pyridin-2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)- benzyl)piperazine- 2,5-dione 704

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-methyl-benzyl)-3-(oxetan-3-yl)- piperazine-2,5-dione 705

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-methyl-benzyl)-3-(oxetan-3- yl)piperazine-2,5-dione 706

3-fluoro-4-(4-(4-fluoro- benzyl)-3-(oxetan-3-yl)- 2,5-dioxopiperazin-1-yl)benzonitrile 707

1-(5-bromo-3-fluoropyridin- 2-yl)-4-(4-fluorobenzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 708

1-(5-bromo-3-fluoropyridin- 2-yl)-4-(4-chlorobenzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 709

(S)-1-(3-fluoro-5-methoxy- pyridin-2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 710

(R)-1-(3-fluoro-5-methoxy- pyridin-2-yl)-3-(oxeldn-3-yl)-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 711

1-(5-(difluoromethoxy)-3- fluoropyridin-2-yl)-3- (oxetan-3-yl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 712

(S)-1-(5-(difluoromethoxy)- 3-fluoropyridin-2-yl)-3- (oxetan-3-yl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 713

(R)-1-(5-(difluoromethoxy)- 3-fluoropyridin-2-yl)-3- (oxetan-3-yl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 714

1-(5-chloro-3-methylpyridin- 2-yl)-4-(4-fluorobenzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 715

(S)-1-(5-chloro-3-methyl- pyridin-2-yl)-4-(4-fluoro-benzyl)-3-(oxetan-3-yl)- piperazine-2,5-dione 716

(R)-1-(5-chloro-3-methyl- pyridin-2-yl)-4-(4-fluoro-benzyl)-3-(oxetan-3-yl)- piperazine-2,5-dione 717

1-(5-chloro-3-methyl- pyridin-2-yl)-4-(3-chloro-4-fluorobenzyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 718

(S)-1-(5-chloro-3-methyl- pyridin-2-yl)-4-(3- chloro-4-fluorobenzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 719

(R)-1-(5-chloro-3-methyl- pyridin-2-yl)-4-(3-chloro-4-fluorobenzyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 720

1-(5-chloro-3-methyl- pyridin-2-yl)-4-(3,4- difluorobenzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 721

(S)-1-(5-chloro-3-methyl- pyridin-2-yl)-4-(3,4-difluorobenzyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 722

(R)-1-(5-chloro-3-methyl- pyridin-2-yl)-4-(3,4-difluorobenzyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 723

4-(4-chlorobenzyl)-1-(3- fluoro-5-vinylpyridin-2-yl)-3-(oxetan-3-yl)piperazine- 2,5-dione 724

1-(5-chloro-3-methyl- pyridin-2-yl)-4-(3-fluoro-4-methylbenzyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 725

(S)-1-(5-chloro-3-methyl- pyridin-2-yl)-4-(3-fluoro-4-methylbenzyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 726

(R)-1-(5-chloro-3-methyl- pyridin-2-yl)-4-(3-fluoro-4-methylberuyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 727

1-(5-chloro-3-methyl- pyridin-2-yl)-4-(4-fluoro-3-methylbenzyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 728

(R)-l-(5-chloro-3-methyl- pyridin-2-yl)-4-(4-fluoro-3-methylbenzyl)-3-(oxetan- 3-yl)piperazine-2,5-dione 729

(S)-1-(5-chloro-3-methyl- pyridin-2-yl)-4-(4-fluoro- 3-methylbenzyl)-3-(oxetan-3-yl)piperazine- 2,5-dione 730

4-(4-chloro-3-fluoro- benzyl)-1-(5-chloro-3- methylpyridin-2-yl)-3-(oxetan-3-yl)-piperazine- 2,5-dione 731

(S)-4-(4-chloro-3-fluoro- benzyl)-1-(5-chloro-3- methylpyridin-2-yl)-3-(oxetan-3-yl)piperazine- 2,5-dione 732

(R)-4-(4-chloro-3-fluoro- benzyl)-1-(5-chloro-3- methylpyridin-2-yl)-3-(oxetan-3-yl)piperazine- 2,5-dione 733

1-(5-chloro-3-methyl- pyridin-2-yl)-4-(4-methyl-benzyl)-3-(oxetan-3-yl)- piperazine-2,5-dione 734

(S)-1-(5-chloro-3-methyl- pyridin-2-yl)-4-(4-methyl-benzyl)-3-(oxetan-3- yl)piperazine-2,5-dione 735

(R)-1-(5-chloro-3-methyl- pyridin-2-yl)-4-(4-methyl-benzyl)-3-(oxetan-3-yl)- piperazine-2,5-dione 736

5-fluoro-6-(3-(oxetan-3- yl)-2,5-dioxo-4-(4- (trifluoromethyl)benzyl)-piperazin-1-yl)nicotinonitrile 737

1-(5-bromo-3-fluoropyridin- 2-yl)-3-((1s,3s)-3-methoxy-cyclobutyl)-4-(4-(trifluoro- methyl)benzyl)piperazine- 2,5-dione 738

1-(5-bromo-3-fluoropyridin- 2-yl)-3-((1r,3r)-3-methoxy-cyclobutyl)-4-(4-(trifluoro- methyl)benzyl)piperazine- 2,5-dione 739

1-(5-chloro-3-fluoropyridin- 2-yl)-3-((1s,3s)-3-hydroxy-cyclobutyl)-4-(4-(trifluoro- methyl)benzyl)piperazine- 2,5-dione 740

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(3-hydroxy-cyclobutyl)-4-(4-(trifluoro- methyl)benzyl)piperazine- 2,5-dione 741

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-fluorobenzyl)-3-((1s,3s)-3-methoxycyclo- butyl)piperazine-2,5-dione 742

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-fluorobenzyl)-3-((1r,3r)-3-methoxycyclo- butyl)piperazine-2,5-dione 743

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-(difluoromethyl)-benzyl)-3-((1s,3s)-3- methoxycyclobutyl)- piperazine-2,5-dione 744

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-(difluoro-methyl)benzyl)-3-((1r,3r)- 3-methoxycyclobutyl)- piperazine-2,5-dione745

(S)-1-(4-chloro-2-fluoro- phenyl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 746

(R)-1-(4-chloro-2-fluoro- phenyl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 747

1-(4-chloro-3-fluorophenyl)- 3-(oxetan-3-yl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 748

(S)-1-(4-chloro-3-fluoro- phenyl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 749

(R)-1-(4-chloro-3-fluoro- phenyl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)- benzyl)piperazine- 2,5-dione 750

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-cyclo- propyl-4-(4-(trifluoro-methyl)benzyl)piperazine- 2,5-dione 751

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-cyclo-propyl-4-(4-fluorobenzyl)- piperazine-2,5-dione 752

(2r,4r)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)- 6,9-dioxo-5,8-diazaspiro-[3.5]nonane-2-carboxamide 753

(2s,4s)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)- 6,9-dioxo-5,8-diazaspiro-[3.5]nonane-2-carboxamide 754

(2r,4r)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4-fluorobenzyl)-6,9-dioxo- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 755

(2s,4s)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4-fluorobenzyl)-6,9-dioxo- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 756

8-(5-chloro-3-fluoropyridin- 2-yl)-5-(4-fluorobenzyl)-2-oxa-5,8-diazaspiro[3.5]- nonane-6,9-dione 757

8-(5-chloro-3-fluoropyrldin- 2-yl)-5-(4-methylbenzyl)-2-oxa-5,8-diazaspiro[3.5]- nonane-6,9-dione 758

1-(3-fluoro-5-methoxy- pyridin-2-yl)-4-(4-methyl-benzyl)-3-(oxetan-3-yl)- piperazine-2,5-dione 759

(S)-1-(3-fluoro-5-methoxy- pyridin-2-yl)-4-(4-methyl-benzyl)-3-(oxetan-3-yl)- piperazine-2,5-dione 760

(R)-1-(3-fluoro-5-methoxy- pyridin-2-yl)-4-(4-methyl-benzyl)-3-(oxetan-3-yl)- piperazine-2,5-dione 761

4-(3-fluoro-4-methyl- benzyl)-1-(3-fluoro-5- methoxypyridin-2-yl)-3-(oxetan-3-yl)piperazine- 2,5-dione 762

(S)-4-(3-fluoro-4-methyl- benzyl)-1-(3-fluoro-5- methoxypyridin-2-yl)-3-(oxetan-3-yl)piperazine- 2,5-dione 763

(R)-4-(3-fluoro-4- methylbenzyl)-1-(3-fluoro- 5-methoxypyridin-2-yl)-3-(oxetan-3-yl)piperazine- 2,5-dione 764

8-(5-chloro-3-fluoropyridin- 2-yl)-5-(4-fluorobenzyl)-2-hydroxy-5,8-diazaspiro- [3.5]nonane-6,9-dione 765

(2r,4r)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4-fluorobenzyl)-2-hydroxy- 5,8-diazaspiro[3.5]nonane- 6,9-dione 766

(2s,4s)-8-(5-chloro-3- fluoropyridin-2-yl)-2- hydroxy-5-(4-methyl-benzyl)-5,8-diazaspiro- [3.5]nonane-6,9-dione 767

(2r,4r)-8-(5-chloro-3- fluoropyridin-2-yl)-2- hydroxy-5-(4-methyl-benzyl)-5,8-diazaspiro- [3.5]nonane-6,9-dione 768

8-(5-chloro-3-fluoropyridin- 2-yl)-5-(4-(difluoromethyl)-benzyl)-2-oxa-5,8- diazaspiro[3.5]nonane- 6,9-dione 769

4-(4-chlorobenzyl)-1-(3- fluoro-5-methoxypyridin- 2-yl)-3-(oxetan-3-yl)-piperazine-2,5-dione 770

(S)-4-(4-chlorobenzyl)-1- (3-fluoro-5-methoxy-pyridin-2-yl)-3-(oxetan-3- yl)piperazine-2,5-dione 771

(R)-4-(4-chlorobenzyl)-1- (3-fluoro-5-methoxy-pyridin-2-yl)-3-(oxetan-3- yl)piperazine-2,5-dione 772

4-(4-chloro-3-fluoro- benzyl)-1-(3-fluoro-5- methoxypyridin-2-yl)-3-(oxetan-3-yl)piperazine- 2,5-dione 773

(S)-4-(4-chloro-3-fluoro- benzyl)-1-(3-fluoro-5- methoxypyridin-2-yl)-3-(oxetan-3-yl)piperazine- 2,5-dione 774

(R)-4-(4-chloro-3-fluoro- benzyl)-1-(3-fluoro-5- methoxypyridin-2-yl)-3-(oxetan-3-yl)piperazine- 2,5-dione 775

4-(3-chloro-4-fluoro- benzyl)-1-(3-fluoro-5- methoxypyridin-2-yl)-3-(oxetan-3-yl)piperazine- 2,5-dione 776

(S)-4-(3-chloro-4-fluoro- benzyl)-1-(3-fluoro-5- methoxypyridin-2-yl)-3-(oxetan-3-yl)piperazine- 2,5-dione 777

(R)-4-(3-chloro-4-fluoro- benzyl)-1-(3-fluoro-5- methoxypyridin-2-yl)-3-(oxetan-3-yl)piperazine- 2,5-dione 778

methyl 3-(4-(5-chloro-3- fluoropyridin-2-yl)-3,6- dioxo-1-(4-(trifluoro-methyl)benzyl)piperazin- 2-yl)bicydo[1.1.1]pentane- 1-carboxylate 779

methyl 3-(4-(5-chloro-3- fluoropyridin-2-yl)-1-(4-(difluoromethyl)benzyl)- 3,6-dioxopiperazin-2- yl)bicyclo[1.1.1]pentane-1-carboxylate 780

methyl 3-(4-(5-chloro-3- fluoropyridin-2-yl)-1-(4- fluorobenzyl)-3,6-dioxopiperazin-2- yl)bicyclo[1.1.1]pentane- 1-carboxylate 781

methyl 3-(4-(5-chloro-3- fluoropyridin-2-yl)-1-(4- methylbenzyl)-3,6-dioxopiperazin-2- yl)bicyclo[1.1.1]pentane- 1-carboxylate 782

ethyl 3-(4-(5-chloro-3- fluoropyridin-2-yl)-3,6- dioxo-1-(4-(trifluoro-methyl)benzyl)piperazin- 2-yl)bicyclo[1.1.1]pentane- 1-carboxylate 783

3-(4-(5-chloro-3-fluoro- pyridin-2-yl)-3,6-dioxo-1-(4-(trifluoromethyl)- benzyl)piperazin-2- yl)bicyclo[1.1.1]pentane-1-carboxamide 784

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(3-(hydroxymethyl)-bicyclo[1.1.1]pentan-1-yl)- 4-(4-(trifluoromethyl)-benzyl)piperazine-2,5-dione 785

2-acetyl-8-(4-chloro-2- fluorophenyl)-5-(4- fluorobenzyl)-2,5,8-triazaspiro[3.5]nonane- 6,9-dione 786

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-((1s,3R)-3-hydroxycyclobutyl)-4- (4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 787

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-((1r,3S)-3-hydroxycyclobutyl)-4- (4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 788

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-((1s,3S)-3-hydroxycydobutyl)-4- (4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 789

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-((1r,3R)-3-hydroxycyclobutyl)-4- (4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 790

3-(4-(5-chloro-3-fluoro- pyridin-2-yl)-1-(4- (difluoromethyl)benzyl)-3,6-dioxopiperazin-2- yl)bicyclo[1.1.1]pentane- 1-carboxamide 791

3-(4-(5-chloro-3-fluoro- pyridin-2-yl)-1-(4-fluoro-benzyl)-3,6-dioxopiperazin- 2-yl)bicyclo[1.1.1]pentane- 1-carboxamide792

3-(4-(5-chloro-3-fluoro- pyridin-2-yl)-1-(4-methyl-benzyl)-3,6-dioxopiperazin- 2-yl)bicyclo[1.1.1]pentane- 1-carboxamide793

(S)-1-(4-chloro-2-fluoro- phenyl)-4-(4-fluorobenzyl)-3-((1s,3R)-3-hydroxy- cyclobutyl)piperazine- 2,5-dione 794

(R)-1-(4-chloro-2-fluoro- phenyl)-4-(4-fluorobenzyl)-3-((1s,3S)-3-hydroxy- cyclobutyl)piperazine- 2,5-dione 795

(S)-1-(4-chloro-2-fluoro- phenyl)-4-(4-fluorobenzyl)-3-((1r,3S)-3-hydroxy- cyclobutyl)-piperazine- 2,5-dione 796

(R)-1-(4-chloro-2-fluoro- phenyl)-4-(4-fluorobenzyl)-3-((1r,3R)-3-hydroxy- cyclobutyl)piperazine- 2,5-dione 797

(2s,4s)-8-(4-chloro-2- fluorophenyl)-5-(4-fluoro- benzyl)-2-hydroxy-5,8-diazaspiro[3.5]nonane- 6,9-dione 798

(2r,4r)-8-(4-chloro-2- fluorophenyl)-5-(4-fluoro- benzyl)-2-hydroxy-5,8-diazaspiro[3.5]nonane- 6,9-dione 799

8-(4-chloro-2-fluoro- phenyl)-5-(4-fluorobenzyl)- 2-oxa-5,8-diazaspiro-[3.5]nonane-6,9-dione 800

(S)-1-(5-chloro-3- fluoropyridin-2-yl)-4-(4- fluorobenzyl)-3-((1s,3R)-3-hydroxycyclobutyl)- piperazine-2,5-dione 801

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-fluoro-benzyl)-3-((1r,3S)-3- hydroxycyclobutyl)- piperazine-2,5-dione 802

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-fluoro-benzyl)-3-((1s,3S)-3- hydroxycyclobutyl)- piperazine-2,5-dione 803

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-fluoro-benzyl)-3-((1r,3R)-3- hydroxycyclobutyl)- piperazine-2,5-dione 804

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-chloro-benzyl)-3-((ls,3R)-3- hydroxycyclobutyl)- piperazine-2,5-dione 805

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-chloro-benzyl)-3-((1r,3S)-3- hydroxycyclobutyl)- piperazine-2,5-dione 806

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-chloro-benzyl)-3-((1s,3S)-3- hydroxycyclobutyl)- piperazine-2,5-dione 807

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-chloro-benzyl)-3-((1r,3R)-3- hydroxycyclobutyl)- piperazine-2,5-dione 808

(2s,4s)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4-fluorobenzyl)-2-hydroxy- 5,8-diazaspiro[3.5]nonane- 6,9-dione 809

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-((1s,3S)-3-hydroxycyclobutyl)-4-(4- methylbenzyl)piperazine- 2,5-dione 810

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-((1r,3R)3-hydroxycyclobutyl)-4- (4-methylbenzyl)- piperazine-2,5-dione 811

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-((1s,3R)-3-hydroxycyclobutyl)-4-(4- methylbenzyl)piperazine- 2,5-dione 812

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-((1r,3S)-3-hydroxycyclobutyl)-4-(4- methylbenzyl)piperazine- 2,5-dione 813

10-(5-chloro-3-fluoro- pyridin-2-yl)-7-(4-(trifluoro-methyl)benzyl)-2-oxa- 7,10-diazadispiro- [3.1.56.14]dodecane- 8,11-dione814

10-(5-chloro-3-fluoro- pyridin-2-yl)-7-(4- (difluoromethyl)benzyl)-2-oxa-7,10-diazadispiro- [3.1.56.14]dodecane- 8,11-dione 815

10-(5-chloro-3-fluoro- pyridin-2-yl)-7-(4- Fluorobenzyl)-2-oxa-7,10-diazadispiro- [3.1.56.14]dodecane- 8,11-dione 816

10-(5-chloro-3-fluoro- pyridin-2-yl)-7-(4-methyl- benzyl)-2-oxa-7,10-diazadispiro[3.1.56.14]- dodecane-8,11-dione 817

(S)-3-(4-(5-chloro-3- fluoropyridin-2-yl)-3,6- dioxo-1-(4-(trifluoro-methyl)benzyl)piperazin- 2-yl)bicyclo[1.1.1]pentane- 1-carboxamide 818

(R)-3-(4-(5-chloro-3- fluoropyridin-2-yl)-3,6- dioxo-1-(4-(trifluoro-methyl)benzyl)piperazin- 2-yl)bicyclo[1.1.1]pentane- 1-carboxamide 819

(S)-3-(4-(5-chloro-3- fluoropyridin-2-yl)-3,6- dioxo-1-(4-fluorobenzyl)-piperazin-2-yl)bicyclo- [1.1.1]pentane-1- carboxamide 820

(R)-3-(4-(5-chloro-3- fluoropyridin-2-yl)-3,6- dioxo-1-(4-fluoro-benzyl)piperazin-2- yl)bicyclo[1.1.1]pentane- 1-carboxamide 821

(S)-3-(4-(5-chloro-3- fluoropyridin-2-yl)-3,6- dioxo-1-(4-(difluoro-methyl)benzyl)piperazin- 2-yl)bicyclo[1.1.1]pentane- 1-carboxamide 822

(R)-3-(4-(5-chioro-3- fluoropyridin-2-yl)-3,6- dioxo-1-(4-(difluoro-methyl)benzyl)piperazin- 2-yl)bicyclo[1.1.1]pentane- 1-carboxamide 823

(S)-3-(4-(5-chloro-3- fluoropyridin-2-yl)-1-(4- methylbenzyl)-3,6-dioxopiperazin-2- yl)bicyclo[1.1.1]pentane- 1-carboxamide 824

(R)-3-(4-(5-chloro-3- fluoropyridin-2-yl)-1-(4- methylbenzyl)-3,6-dioxopiperazin-2-yl)- bicyclo[1.1.1]pentane-1- carboxamide 825

2-acetyl-10-(5-chloro-3- fluoropyridin-2-yl)-7-(4-(trifluoromethyl)benzyl)- 2,7,10-triazadispiro- [3.1.56.14]dodecane-8,11-dione 826

2-acetyl-10-(5-chloro-3- fluoropyridin-2-yl)-7-(4-(difluoromethyl)benzyl)- 2,7,10-triazadispiro- [3.1.56.14]dodecane-8,11-dione 827

2-acetyl-10-(5-chloro-3- fluoropyridin-2-yl)-7-(4- fluorobenzyl)-2,7,10-triazadispiro[3.1.56.14]- dodecane-8,11-dione 828

10-(5-chloro-3-fluoro- pyridin-2-yl)-7-(4-fluoro-benzyl)-8,11-dioxo-2,7,10- triazadispiro[3.1.56.14]-dodecane-2-carbaldehyde 829

2-acetyl-10-(5-chloro-3- fluoropyridin-2-yl)-7-(4- methylbenzyl)-2,7,10-triazadispiro[3.1.56.14]- dodecane-8,11-dione 830

10-(5-chloro-3-fluoro- pyridin-2-yl)-7-(4-methyl-benzyl)-8,11-dioxo-2,7,10- triazadispiro[3.1.56.14]-dodecane-2-carbaldehyde 831

2-acetyl-10-(5-chloro-3- fluoropyridin-2-yl)-7-(4- chlorobenzyl)-2,7,10-triazadispiro[3.1.56.14]- dodecane-8,11-dione 832

10-(5-chloro-3-fluoro- pyridin-2-yl)-7-(4-chloro-benzyl)-8,11-dioxo-2,7,10- triazadispiro[3.1.56.14]-dodecane-2-carbaldehyde 833

(2s,4s)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4-chlorobenzyl)-2-hydroxy- 5,8-diazaspiro[3.5]nonane- 6,9-dione 834

(2r,4r)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4-chlorobenzyl)-2-hydroxy- 5,8-diazaspiro[3.5]nonane- 6,9-dione 835

3-(4-(5-chloro-3-fluoro- pyridin-2-yl)-1-(4-chloro-benzyl)-3,6-dioxopiperazin- 2-yl)bicydo[1.1.1]pentane- 1-carboxamide 836

(S)-3-(4-(5-chloro-3-fluoro- pyridin-2-yl)-1-(4-chloro-benzyl)-3,6-dioxo-piperazin- 2-yl)bicyclo-[1.1.1]pentane- 1-carboxamide837

(R)-3-(4-(5-chloro-3-fluoro- pyridin-2-yl)-1-(4-chloro-benzyl)-3,6-dioxo- piperazin-2-yl)bicyclo- [1.1.1]pentane-1- carboxamide838

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(3-hydroxy-bicydo[1.1.1]pentan-1-yl)- 4-(4-(trifluoromethyl)- benzyl)piperazine-2,5-dione 839

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(3-hydroxy-bicyclo[1.1.1]pentan-1-yl- 4-(4-(trifluoromethyl)-benzyl)piperazine-2,5-dione 840

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(3-hydroxy-bicyclo[1.1.1]pentan-1-yl)- 4-(4-(trifluoromethyl)-benzyl)piperazine-2,5-dione 841

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-chlorobenzyl)-3-(3-hydroxybicyclo[1.1.1]- pentan-1-yl)piperazine- 2,5-dione 842

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-chloro-benzyl)-3-(3-hydroxy- bicyclo[1.1.1]pentan-1- yl)piperazine-2,5-dione843

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-chloro-benzyl)-3-(3-hydroxy- bicyclo-[1.1.1]pentan-1- yl)piperazine-2,5-dione844

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-fluorobenzyl)-3-(3-hydroxybicyclo[1.1.1]- pentan-1-yl)piperazine- 2,5-dione 845

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-fluoro-benzyl)-3-(3-hydroxy- bicyclo[1.1.1]pentan-1- yl)piperazine-2,5-dione846

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4-fluoro-benzyl)-3-(3-hydroxy- bicydo[1.1.1]pentan-1- yl)piperazine-2,5-dione 847

(2s,4s)-8-(5-chloropyridin- 2-yl)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5- (4-fluorobenzyl)-5,8- diazaspiro[3.5]nonane-6,9-dione 848

(2r,4r)-8-(5-chloropyridin- 2-yl)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5- (4-fluorobenzyl)-5,8- diazaspiro[3.5]nonane-6,9-dione 849

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-(difluoromethyl)-benzyl)-3-(3-hydroxy- bicyclo[1.1.1]pentan-1- yl)piperazine-2,5-dione850

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4- (difluoromethyl)benzyl)-3-(3-hydroxybicyclo[1.1.1]- pentan-1-yl)piperazine- 2,5-dione 851

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-4-(4- (difluoromethyl)benzyl)-3-(3-hydroxybicyclo[1.1.1]- pentan-1-yl)piperazine- 2,5-dione 852

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(3-hydroxybicyclo-[1.1.1]pentan-1-yl)-4-(4- methylbenzyl)piperazine- 2,5-dione 853

(S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(3- hydroxybicydo[1.1.1]-pentan-1-yl)-4-(4-methyl- benzyl)piperazine- 2,5-dione 854

(R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(3- hydroxybicydo[1.1.1]-pentan-1-yl)-4-(4- methylbenzyl)piperazine- 2,5-dione 855

(2s,4s)-8-(5-chloropyridin- 2-yl)-5-(4-fluorobenzyl)-2-(1,3,4-oxadiazol-2-yl)-5,8- diazaspiro[3.5]nonane- 6,9-dione 856

(2r,4r)-8-(5-chloropyridin- 2-yl)-5-(4-fluorobenzyl)-2-(1,3,4-oxadiazol-2-yl)-5,8- diazaspiro[3.5]nonane- 6,9-dione 857

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(hydroxymethyl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 858

1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(1-hydroxy-ethyl)-4-(4-(trifluoro- methyl)benzyl)piperazine- 2,5-dione 859

ethyl 8-(5-chloro-3-fluoro- pyridin-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxylate860

ethyl 8-(5-chloro-3-fluoro- pyridin-2-yl)-5-(4-chloro-benzyl)-6,9-dioxo-5,8- diazaspiro[3.5]nonane- 2-carboxylate 861

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)benzyl)- piperazine-2,5-dione 862

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-chlorobenzyl)-3-(hydroxymethyl)piperazine- 2,5-dione 863

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-chlorobenzyl)-3-isopropylpiperazine-2,5- dione 864

1-(5-chloro-3-fluoropyridin- 2-yl)-3-isopropyl-4-((S)-1-(4-(trifluoromethyl)phenyl)- ethyl)piperazine-2,5-dione 865

(6S)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(hydroxy-methyl)-6-methyl-4-(4- (trifluoromethyl)benzyl)- piperazine-2,5-dione866

1-(4-chloro-2-fluoro- phenyl)-4-(4-fluoro- benzyl)-3-(3-hydroxy-cyclobutyl)piperazine- 2,5-dione 867

8-(4-chloro-2-fluoro- phenyl)-5-(4-fluorobenzyl)-2-hydroxy-5,8-diazaspiro- [3.5]nonane-6,9-dione 868

8-(5-chloro-3-fluoropyridin- 2-yl)-2-hydroxy-5-(4- methylbenzyl)-5,8-diazaspiro[3.5]nonane- 6,9-dione 869

8-(5-chloro-3-fluoropyridin- 2-yl)-5-(4-chlorobenzyl)-2-hydroxy-5,8-diazaspiro- [3.5]nonane-6,9-dione 870

8-(5-chloro-3-fluoropyridin- 2-yl)-N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide871

8-(5-chloro-3-fluoropyridin- 2-yl)-N,N-dimethyl-6,9-dioxo-5-(4-(trifluoro- methyl)benzyl)-5,8- diazaspiro[3.5]nonane-2-carboxamide 872

8-(5-chloro-3-fluoropyridin- 2-yl)-5-(4-chlorobenzyl)- 6,9-dioxo-5,8-diazaspiro[3.5]nonane- 2-carboxamide 873

8-(5-chloro-3-fluoro- pyridin-2-yl)-5-(4-chloro- benzyl)-N-methyl-6,9-dioxo-5,8-diazaspiro- [3.5]nonane-2- carboxamide 874

8-(5-chloro-3-fluoropyridin- 2-yl)-5-(4-chlorobenzyl)-N,N-dimethyl-6,9-dioxo- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 875

8-(5-chloro-3-fluoropyridin- 2-yl)-5-(4-(difluoro-methyl)benzyl)-6,9-dioxo- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 876

8-(5-chloro-3-fluoropyridin- 2-yl)-5-(4-fluorobenzyl)-6,9-dioxo-5,8-diazaspiro- [3.5]nonane-2-carboxamide 877

8-(5-chloro-3-fluoropyridin- 2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide 878

8-(5-chloro-3-methyl- pyridin-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane- 2-carboxamide879

8-(5-chloropyridin-2-yl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane- 2-carboxamide 880

8-(5-chloropyridin-2-yl)- 2-(5-cyclopropyl-1,3,4- oxadiazol-2-yl)-5-(4-fluorobenzyl)-5,8- diazaspiro[3.5]nonane- 6,9-dione 881

8-(5-chloropyridin-2-yl)-5- (4-fluorobenzyl)-2-(1,3,4-oxadiazol-2-yl)-5,8- diazaspiro[3.5]nonane- 6,9-dione 882

8-(5-chloro-3-methyl- pyridin-2-yl)-5-(4-chloro-benzyl)-2-(pyridin-2-yl)- 2,5,8-triazaspiro[3.5]- nonane-6,9-dione 883

8-(5-chloro-3-methyl- pyridin-2-yl)-5-(4-fluoro-benzyl)-2-(pyridin-2-yl)- 2,5,8-triazaspiro[3.5]- nonane-6,9-dione 884

8-(5-chloro-3-methyl- pyridin-2-yl)-5-(4-chloro-benzyl)-2-(5-fluoropyridin- 2-yl)-2,5,8-triazaspiro[3.5]-nonane-6,9-dione 885

8-(5-chloro-3-methyl- pyridin-2-yl)-5-(4-fluoro-benzyl)-2-(5-fluoropyridin- 2-yl)-2,5,8-triazaspiro-[3.5]nonane-6,9-dione 886

6-(8-(5-chloro-3-methyl- pyridin-2-yl)-5-(4-chloro-benzyl)-6,9-dioxo-2,5,8- triazaspiro[3.5]nonan-2- yl)nicotinonitrile 887

6-(8-(5-chloro-3-methyl- pyridin-2-yl)-5-(4-fluoro-benzyl)-6,9-dioxo-2,5,8- triazaspiro[3.5]nonan-2- yl)nicotinonitrile 888

(6R)-1-(5-chloro-3-fluoro- pyridin-2-yl)-3-(hydroxy-methyl)-6-methyl-4-(4- (trifluoromethyl)benzyl)- piperazine-2,5-dione889

1-(5-bromo-3-fluoro- pyridin-2-yl)-3-(3-methoxy-cyclobutyl)-4-(4-(trifluoro- methyl)benzyl)piperazine- 2,5-dione 890

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-fluorobenzyl)-3-(3-methoxycyclobutyl)- piperazine-2,5-dione 891

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-(difluoromethyl)-benzyl)-3-(3-methoxycyclo- butyl)piperazine-2,5-dione 892

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-fluorobenzyl)-3-(3-hydroxycyclobutyl)- piperazine-2,5-dione 893

1-(5-chloro-3-fluoropyridin- 2-yl)-4-(4-chlorobenzyl)-3-(3-hydroxycyclobutyl)- piperazine-2,5-dione 894

1-(5-chloro-3-fluoropyridin- 2-yl)-3-(3-hydroxycyclo-butyl)-4-(4-methylbenzyl)- piperazine-2,5-dione

In some variations, any of the compounds described herein, such as acompound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or anyvariation thereof, or a compound of Table 1 may be deuterated (e.g., ahydrogen atom is replaced by a deuterium atom). In some of thesevariations, the compound is deuterated at a single site. In othervariations, the compound is deuterated at multiple sites. Deuteratedcompounds can be prepared from deuterated starting materials in a mannersimilar to the preparation of the corresponding non-deuteratedcompounds. Hydrogen atoms may also be replaced with deuterium atomsusing other method known in the art.

Any formula given herein, such as Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1),or (In-2), is intended to represent compounds having structures depictedby the structural formula as well as certain variations or forms. Inparticular, compounds of any formula given herein may have asymmetriccenters and therefore exist in different enantiomeric or diastereomericforms. All optical isomers and stereoisomers of the compounds of thegeneral formula, and mixtures thereof in any ratio, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof in any ratio. Where a compound of Table 1 is depicted with aparticular stereochemical configuration, also provided herein is anyalternative stereochemical configuration of the compound, as well as amixture of stereoisomers of the compound in any ratio. For example,where a compound of Table 1 has a stereocenter that is in an “S”stereochemical configuration, also provided herein is enantiomer of thecompound wherein that stereocenter is in an “R” stereochemicalconfiguration. Likewise, when a compound of Table 1 has a stereocenterthat is in an “R” configuration, also provided herein is enantiomer ofthe compound in an “S” stereochemical configuration. Also provided aremixtures of the compound with both the “S” and the “R” stereochemicalconfiguration. Additionally, if a compound of Table 1 has two or morestereocenters, also provided are any enantiomer or diastereomer of thecompound. For example, if a compound of Table 1 contains a firststereocenter and a second stereocenter with “R” and “R” stereochemicalconfigurations, respectively, also provided are stereoisomers of thecompound having first and second stereocenters with “S” and “S”stereochemical configurations, respectively, “S” and “R” stereochemicalconfigurations, respectively, and “R” and “S” stereochemicalconfigurations, respectively. If a compound of Table 1 contains a firststereocenter and a second stereocenter with “S” and “S” stereochemicalconfigurations, respectively, also provided are stereoisomers of thecompound having first and second stereocenters with “R” and “R”stereochemical configurations, respectively, “S” and “R” stereochemicalconfigurations, respectively, and “R” and “S” stereochemicalconfigurations, respectively. If a compound of Table 1 contains a firststereocenter and a second stereocenter with “S” and “R” stereochemicalconfigurations, respectively, also provided are stereoisomers of thecompound having first and second stereocenters with “R” and “S”stereochemical configurations, respectively, “R” and “R” stereochemicalconfigurations, respectively, and “S” and “S” stereochemicalconfigurations, respectively. Similarly, if a compound of Table 1contains a first stereocenter and a second stereocenter with “R” and “S”stereochemical configurations, respectively, also provided arestereoisomers of the compound having first and second stereocenters with“S” and “R” stereochemical configurations, respectively, “R” and “R”stereochemical configurations, respectively, and “S” and “S”stereochemical configurations, respectively. Furthermore, certainstructures may exist as geometric isomers (i.e., cis and trans isomers),as tautomers, or as atropisomers. Additionally, any formula given hereinis intended to refer also to any one of hydrates, solvates, andamorphous and polymorphic forms of such compounds, and mixtures thereof,even if such forms are not listed explicitly. In some embodiments, thesolvent is water and the solvates are hydrates.

Representative examples of compounds detailed herein, includingintermediates and final compounds, are depicted in the tables andelsewhere herein. It is understood that in one aspect, any of thecompounds may be used in the methods detailed herein, including, whereapplicable, intermediate compounds that may be isolated and administeredto an individual or subject.

The compounds depicted herein may be present as salts even if salts arenot depicted, and it is understood that the compositions and methodsprovided herein embrace all salts and solvates of the compounds depictedhere, as well as the non-salt and non-solvate form of the compound, asis well understood by the skilled artisan. In some embodiments, thesalts of the compounds provided herein are pharmaceutically acceptablesalts.

In one variation, the compounds herein are synthetic compounds preparedfor administration to an individual or subject. In another variation,compositions are provided containing a compound in substantially pureform. In another variation, provided are pharmaceutical compositionscomprising a compound detailed herein and a pharmaceutically acceptablecarrier. In another variation, methods of administering a compound areprovided. The purified forms, pharmaceutical compositions and methods ofadministering the compounds are suitable for any compound or formthereof detailed herein.

Any variation or embodiment of G¹, R¹, R^(2A), R^(2B), R³, R⁴, and R⁵provided herein R^(2A), R^(2B), R³, R⁴, and can be combined with everyother variation or embodiment of G¹, R¹, R⁵, as if each combination hadbeen individually and specifically described.

Any variation or embodiment of G¹, R¹, R^(2A), R^(2B), R³, R⁴, R⁵,R^(1a), R^(2a), R^(2b), R^(3a), m, n, p, q, X, and Q provided herein canbe combined with every other variation or embodiment of G¹, R¹, R^(2A),R^(2B), R³, R⁴, R⁵, R^(1a), R^(2a), R^(2b), R^(1a) m, n, p, q, X, and Q,as if each combination had been individually and specifically described.

As used herein, when any variable occurs more than one time in achemical formula, its definition on each occurrence is independent ofits definition at every other occurrence.

Formula (I) includes all subformulae thereof. For example, Formula (I)includes compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2).

Certain compound names provided herein, including in Table 1, areprovided by ChemBioDraw Professional 15.0.0.106. One of skilled in theart would understand that the compounds may be named or identified usingvarious commonly recognized nomenclature systems and symbols. By way ofexample, the compounds may be named or identified with common names,systematic or non-systematic names. The nomenclature systems and symbolsthat are commonly recognized in the art of chemistry include, forexample, Chemical Abstract Service (CAS), ChemBioDraw Ultra, andInternational Union of Pure and Applied Chemistry (IUPAC).

Compositions

Also provided are compositions, such as pharmaceutical compositions,that include a compound disclosed and/or described herein and one ormore additional medicinal agents, pharmaceutical agents, adjuvants,carriers, excipients, and the like. Suitable medicinal andpharmaceutical agents include those described herein. In someembodiments, the pharmaceutical composition includes a pharmaceuticallyacceptable excipient or adjuvant and at least one chemical entity asdescribed herein. Examples of pharmaceutically acceptable excipientsinclude, but are not limited to, mannitol, lactose, starch, magnesiumstearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose,glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments,provided are compositions, such as pharmaceutical compositions thatcontain one or more compounds described herein, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, provided is a pharmaceutically acceptablecomposition comprising a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im),(In-1), or (In-2), or a compound of Table 1, or a pharmaceuticallyacceptable salt thereof. In some aspects, a composition may contain asynthetic intermediate that may be used in the preparation of a compounddescribed herein. The compositions described herein may contain anyother suitable active or inactive agents.

Any of the compositions described herein may be sterile or containcomponents that are sterile. Sterilization can be achieved by methodsknown in the art. Any of the compositions described herein may containone or more compounds or conjugates that are substantially pure.

Also provided are packaged pharmaceutical compositions, comprising apharmaceutical composition as described herein and instructions forusing the composition to treat a patient suffering from a disease orcondition described herein.

Methods of Use

The compounds and pharmaceutical compositions herein may be used totreat or prevent a disease or condition in an individual or subject.

When used in a prophylactic manner, the compounds disclosed and/ordescribed herein may prevent a disease or disorder from developing orlessen the extent of a disease or disorder that may develop in anindividual or subject at risk of developing the disease or disorder.

Without being bound by theory, the compounds and pharmaceuticalcompositions disclosed herein are believed to act by inhibiting myosin.This inhibition potentially decreases the number of independent myosinheads interacting with actin filaments reducing the amount ofcontraction. Reducing contraction of cardiac muscle can be important forthe treatment of heart diseases in which over-contraction is an issue.In some embodiments, provided are methods of treating or preventingheart disease in an individual or subject, comprising administering tothe individual or subject in need thereof a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1),(Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1, or apharmaceutically acceptable salt thereof. In some embodiments, providedare methods of treating or preventing heart disease in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of at least one chemical entity as described herein. Insome embodiments, provided are methods of treating heart disease in asubject in need thereof comprising administering to the subject atherapeutically effective amount of at least one chemical entity asdescribed herein. In some embodiments, provided are methods of treatingan established or diagnosed heart disease in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of at least one chemical entity as described herein. In someembodiments, provided are methods of preventing heart disease in asubject in need thereof comprising administering to the subject atherapeutically effective amount of at least one chemical entity asdescribed herein.

Also provided herein is the use of a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2),(Il), (Im), (In-1), or (In-2), or a compound of Table 1, or apharmaceutically acceptable salt thereof in the manufacture of amedicament for treatment of a heart disease in a subject. In someaspects, provided is a compound or composition as described herein foruse in a method of treatment of the human or animal body by therapy. Insome embodiments, provided herein are compounds of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2),(Il), (Im), (In-1), or (In-2), or a compound of Table 1, or apharmaceutically acceptable salt thereof, for use in a method oftreatment of the human or animal body by therapy. In some embodiments,provided herein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound ofTable 1, or a pharmaceutically acceptable salt thereof, for use intreating or preventing heart disease. In some embodiments, providedherein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If),(Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, ora pharmaceutically acceptable salt thereof, for use in treating heartdisease. In some embodiments, provided herein are compounds of Formula(I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1),or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptablesalt thereof, for use in treating an established or diagnosed heartdisease. In other embodiments, provided herein are compounds of Formula(I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1),or (Ik-2), or a compound of Table 1, or a pharmaceutically acceptablesalt thereof, for use in preventing heart disease. In some embodiments,provided herein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound ofTable 1, or a pharmaceutically acceptable salt thereof, for use intreating a disease or condition associated with HCM. In someembodiments, provided herein are compounds of Formula (I), (Ia), (Ib),(Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or acompound of Table 1, or a pharmaceutically acceptable salt thereof, foruse in treating a disease or condition associated with secondary leftventricular wall thickening. In some embodiments, provided herein arecompounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or apharmaceutically acceptable salt thereof, for use in ameliorating asymptom associated with heart disease. In other embodiments, providedherein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If),(Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, ora pharmaceutically acceptable salt thereof, for use in reducing the riskof a symptom associated with heart disease. In other embodiments,provided herein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound ofTable 1, or a pharmaceutically acceptable salt thereof, for use intreating a disease or condition associated with small left ventricularcavity, cavity obliteration, hyperdynamic left ventricular contraction,obstruction of blood flow out of the left ventricle, cardiachypertrophy, small cardiac stroke volume, impaired relaxation of theleft ventricle, high left ventricle filling pressure, myocardialischemia, or cardiac fibrosis. In certain embodiments, provided hereinare compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or apharmaceutically acceptable salt thereof, for use in treating a diseaseor condition associated with small left ventricular cavity and cavityobliteration, hyperdynamic left ventricular contraction, myocardialischemia, or cardiac fibrosis. In some embodiments, provided herein arecompounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or apharmaceutically acceptable salt thereof, for use in treating musculardystrophies. In some embodiments, provided herein are compounds ofFormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceuticallyacceptable salt thereof, for use in treating a glycogen storage disease.In other embodiments, provided herein are compounds of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or(Ik-2), or a compound of Table 1, or a pharmaceutically acceptable saltthereof, for use in modulating the cardiac sarcomere, such as inhibitingthe cardiac sarcomere. In yet other embodiments, provided herein arecompounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or a compound of Table 1, or apharmaceutically acceptable salt thereof, for use in potentiatingcardiac myosin.

In some embodiments, the subject is a mammal. In some embodiments, thesubject is a mouse, rat, dog, cat, pig, sheep, horse, cow, or human. Insome embodiments, the subject is a human. In some embodiments, thesubject has an established or diagnosed heart disease. In someembodiments, the subject has established or diagnosed hypertrophiccardiomyopathy (HCM). In some embodiments, the subject is at risk fordeveloping heart disease. In some embodiments, the subject has amutation that increases risk for heart disease. In some embodiments, thesubject has a mutation that increases risk for hypertrophiccardiomyopathy (HCM). In some embodiments, the mutation is a sarcomericmutation. In some embodiments, the mutation is a mutation in myosinheavy chain β (MHC-β), cardiac muscle troponin T (cTnT), tropomyosinalpha-1 chain (TPM1), myosin-binding protein C cardiac-type (MYBPC3),cardiac troponin I (cTnI), myosin essential light chain (ELC), titin(TTN), myosin regulatory light chain 2 ventricular/cardiac muscleisoform (MLC-2), cardiac muscle alpha actin, muscle LIM protein (MLP),or protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2).In some embodiments, the mutation is a mutation in MHC-β. In someembodiments, the subject has established or diagnosed hypertrophiccardiomyopathy without a confirmed genetic etiology.

In some embodiments, the subject has a high risk of progressivesymptoms. In some embodiments, the subject has a high risk of atrialfibrillation, ventricular tachyarrhythmias, stroke, and/or sudden death.In some embodiments, the subject has a reduced exercise capacity. Insome embodiments, the reduced exercise capacity is as compared to anage-matched control population. In some embodiments, the subject iseligible for surgical intervention or percutaneous ablation to treat theheart disease.

In some embodiments, the heart disease is hypertrophic cardiomyopathy(HCM). In some embodiments, the heart disease is obstructive HCM. Insome embodiments, the heart disease is nonobstructive HCM. In someembodiments, the HCM is associated with a sarcomeric mutation. In someembodiments, the HCM is associated with a non-sarcomeric mutation. Insome embodiments, the heart disease is obstructive or nonobstructive HCMcaused by sarcomeric and/or non-sarcomeric mutations. In someembodiments, the sarcomeric mutation is a mutation in a myosin heavychain β (MHC-β), cardiac muscle troponin T (cTnT), tropomyosin alpha-1chain (TPM1), myosin-binding protein C cardiac-type (MYBPC3), cardiactroponin I (cTnI), myosin essential light chain (ELC), titin (TTN),myosin regulatory light chain 2 ventricular/cardiac muscle isoform(MLC-2), cardiac muscle alpha actin, or muscle LIM protein (MLP). Insome embodiments, the sarcomeric mutation is a mutation in MHC-β. Insome embodiments, the non-sarcomeric mutation is a mutation in proteinkinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2).

In some embodiments, provided herein are methods of treating a diseaseor condition associated with HCM, comprising administering to theindividual or subject in need thereof a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2),(Il), (Im), (In-1), or (In-2), or a compound of Table 1, or apharmaceutically acceptable salt thereof. In some embodiments, thedisease or condition is Fabry's Disease, Danon Disease, mitochondrialcardiomyopathies, or Noonan Syndrome.

Also provided herein is the use of a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2),(Il), (Im), (In-1), or (In-2), or a compound of Table 1, or apharmaceutically acceptable salt thereof in the manufacture of amedicament for treatment of a disease or condition associated with HCM.

In some embodiments, the heart disease is heart failure with preservedejection fraction (HFpEF). In some embodiments, the heart disease isdiastolic dysfunction. In some embodiments, the heart disease iscardiomyopathy. In some embodiments, the heart disease is primary orsecondary restrictive cardiomyopathy. In some embodiments, the heartdisease is condition or symptoms caused by coronary artery disease. Insome embodiments, the heart disease is myocardial infarction or anginapectoris. In some embodiments, the heart disease is left ventricularoutflow tract obstruction. In some embodiments, the heart disease ishypertensive heart disease. In some embodiments, the heart disease iscongenital heart disease. In some embodiments, the heart disease iscardiac ischemia and/or coronary heart disease. In some embodiments, theheart disease is diabetic heart disease. In other embodiments, the heartdisease is congestive heart failure. In some embodiments, the heartdisease is right heart failure. In other embodiments, the heart diseaseis cardiorenal syndrome. In some embodiments, the heart disease isinfiltrative cardiomyopathy. In some embodiments, the heart disease is acondition that is or is related to cardiac senescence or diastolicdysfunction due to aging. In some embodiments, the heart disease is acondition that is or is related to left ventricular hypertrophy and/orconcentric left ventricular remodeling.

In some embodiments, the provided are methods of treating a disease orcondition associated with secondary left ventricular wall thickening inan individual or subject, comprising administering to the individual orsubject in need thereof a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im),(In-1), or (In-2), or a compound of Table 1, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the disease ishypertension, valvular heart diseases (aortic stenosis, Mitral valveregurgitation), metabolic syndromes (diabetes, obesity), end stage renaldisease, scleroderma, sleep apnea, amyloidosis, Fabry's disease,Friedreich Ataxia, Danon disease, Noonan syndrome, or Pompe disease.

Also provided herein is the use of a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2),(Il), (Im), (In-1), or (In-2), or a compound of Table 1, or apharmaceutically acceptable salt thereof in the manufacture of amedicament for treatment of a disease or condition associated withsecondary left ventricular wall thickening.

In some embodiments, provided are methods of ameliorating a symptomassociated with heart disease in a subject, comprising administering tothe individual or subject in need thereof a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or(Ik-2), or a compound of Table 1, or a pharmaceutically acceptable saltthereof, wherein the symptom is one or more selected from poor orreduced cardiac elasticity, poor or reduced diastolic left ventricularrelaxation, abnormal left atrial pressure (e.g., abnomally high leftatrial pressure), paroxysmal or permanent atrial fibrillation, increasedleft atrial and pulmonary capillary wedge pressures, increased leftventricular diastolic pressures, syncope, ventricular relaxation duringdiastole, ventricular fibrosis, left ventricular hypertrophy, leftventricular mass, increased left ventricular wall thickness, leftventricular mid-cavity obstruction, increased systolic anterior motionof mitral valve, left ventricular outflow tract obstruction, chest pain,exertional dyspnea, pre-syncope, abnormal exercise capacity, andfatigue.

In some embodiments, the provided are methods of reducing the risk of asymptom associated with heart disease in a subject, comprisingadministering to the individual or subject in need thereof a compound ofFormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(Ik-1), or (Ik-2), or a compound of Table 1, or a pharmaceuticallyacceptable salt thereof, wherein the symptom is one or more selectedfrom sudden cardiac death, poor or reduced cardiac elasticity, poor orreduced diastolic left ventricular relaxation, abnormal left atrialpressure (e.g., abnomally high left atrial pressure), paroxysmal orpermanent atrial fibrillation, increased left atrial and pulmonarycapillary wedge pressures, increased left ventricular diastolicpressures, syncope, ventricular relaxation during diastole, ventricularfibrosis, left ventricular hypertrophy, left ventricular mass, increasedleft ventricular wall thickness, left ventricular mid-cavityobstruction, increased systolic anterior motion of mitral valve, leftventricular outflow tract obstruction, chest pain, exertional dyspnea,pre-syncope, abnormal exercise capacity, and fatigue.

In some embodiments, the provided are methods of treating a disease orcondition associated with small left ventricular cavity, cavityobliteration, hyperdynamic left ventricular contraction, obstruction ofblood flow out of the left ventricle, cardiac hypertrophy, small cardiacstroke volume, impaired relaxation of the left ventricle, high leftventricle filling pressure, myocardial ischemia, or cardiac fibrosis inan individual or subject, comprising administering to the individual orsubject in need thereof a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), or (Ik-2), or acompound of Table 1, or a pharmaceutically acceptable salt thereof.

In some embodiments, provided are methods of treating a disease orcondition associated with small left ventricular cavity and cavityobliteration, hyperdynamic left ventricular contraction, myocardialischemia, or cardiac fibrosis in an individual or subject, comprisingadministering to the individual or subject in need thereof a compound ofFormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1,or a pharmaceutically acceptable salt thereof.

Also provided herein is the use of a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2),(Il), (Im), (In-1), or (In-2), or a compound of Table 1, or apharmaceutically acceptable salt thereof in the manufacture of amedicament for treatment of a disease or condition associated with smallleft ventricular cavity and cavity obliteration, hyperdynamic leftventricular contraction, myocardial ischemia, or cardiac fibrosis.

In some embodiments, the provided are methods of treating musculardystrophies in an individual or subject (e.g., Duchenne musculardystrophy), comprising administering to the individual or subject inneed thereof a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or(In-2), or a compound of Table 1, or a pharmaceutically acceptable saltthereof. Also provided herein is the use of a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1),(Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1, or apharmaceutically acceptable salt thereof in the manufacture of amedicament for treatment of muscular dystrophies (e.g., Duchennemuscular dystrophy).

In some embodiments, the provided are methods of treating a glycogenstorage disease in an individual or subject, comprising administering tothe individual or subject in need thereof a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1),(Ik-2), (Il), (Im), (In-1), or (In-2), or a compound of Table 1, or apharmaceutically acceptable salt thereof. Also provided herein is theuse of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If),(Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2),or a compound of Table 1, or a pharmaceutically acceptable salt thereofin the manufacture of a medicament for treatment of a glycogen storagedisease.

Also provided are methods for modulating the cardiac sarcomere in anindividual or subject which method comprises administering to anindividual or subject in need thereof a therapeutically effective amountof at least one chemical entity as described herein. In someembodiments, provided are methods of inhibiting the cardiac sarcomere,comprising contacting the cardiac sarcomere with at least one chemicalentity as described herein, such as a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2),(Il), (Im), (In-1), or (In-2), or a compound of Table 1, or apharmaceutically acceptable salt thereof. Additionally provided hereinis the use of at least one chemical entity as described herein, such asa compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or acompound of Table 1, or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for inhibiting the cardiac sarcomere ofan individual or subject.

Also provided are methods for potentiating cardiac myosin in anindividual or subject which method comprises administering to anindividual or subject in need thereof a therapeutically effective amountof at least one chemical entity as described herein such as a compoundof Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii),(Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or (In-2), or a compound ofTable 1, or a pharmaceutically acceptable salt thereof. Additionallyprovided herein is the use of at least one chemical entity as describedherein, such as a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), or(In-2), or a compound of Table 1, or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for potentiating cardiacmyosin in an individual or subject.

In some embodiments, the methods provided herein further comprisemonitoring the effectiveness of the treatment. Examples of indicatorsinclude, but are not limited to improvement in one or more of thefollowing: New York Heart Association (NYHA) Functional Classification,exercise capacity, cardiac elasticity, diastolic left ventricularrelaxation, left atrial pressure, paroxysmal or permanent atrialfibrillation, left atrial and pulmonary capillary wedge pressures, leftventricular diastolic pressures, syncope, ventricular relaxation duringdiastole, ventricular fibrosis, left ventricular hypertrophy, leftventricular mass, left ventricular wall thickness, left ventricularmid-cavity obstruction systolic anterior motion of mitral valve, leftventricular outflow tract obstruction, chest pain, exertional dyspnea,pre-syncope, abnormal exercise capacity, and fatigue. These indicatorscan be monitored by techniques known in the art includingself-reporting; ECG, including ambulatory ECG; echocardiography; cardiacMRI; CT; biopsy; cardiopulmonary exercise testing (CPET); andactigraphy.

In some embodiments, the compound reduces the contractility of acardiomyocyte. In some embodiments, the compound reduces thecontractility of a cardiomyocyte by greater than 40%, such as greaterthan 45%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the compoundreduced the contractility of a cardiomyocyte 40%-90%, such as 40%-80%,40-70%, 50%-90%, 50%-80% or 50%-70%. In some embodiments, the compounddoes not significantly alter calcium transients in the cardiomyocyte. Insome embodiments, the compound decreases the ATPase activity in acardiomyocyte. Methods of measuring contractility, ATPase activity, andcalcium transients are known in the art, for example, by calciumlabeling, electrophysiological recordings, and microscopic imaging. Insome embodiments, the compound does not significantly inhibit or inducea cytochrome P450 (CYP) protein.

Without being bound by theory, it is believed that the stereoisomer of acompound of Formula (I) or any variation thereof in which the carbonbearing the R^(2A) and R^(2B) moieties is in the “S” stereochemicalconfiguration is more active as measured by a myofibril assay (such asthe assay described in Example B-1) than the corresponding stereoisomerin which the carbon bearing the R^(2A) and R^(2B) moieties is in the “R”stereochemical configuration. A crystal structure was obtained for arepresentative compound of Formula (I), demonstrating that, as betweenthe “S” isomer and the “R” isomer, the more active stereoisomer, asmeasured by the myofibril assay described in Example B-1, is thestereoisomer in which the carbon bearing the R^(2A) and R^(2B) moietiesis in the “S” stereochemical configuration.

In some embodiments, the subject has a left ventricular wall that isthicker than normal prior to treatment. In some embodiments, the subjecthas a left ventricular wall thickness that is greater than 15 mm, suchas greater than 18 mm, 20 mm, 22 mm, 25 mm, or 30 mm prior to treatment.In some embodiments, the left ventricular wall thickness is reduced bygreater than 5%, such as greater than 8%, 10%, 12%, 15%, 20%, or 30%following treatment. Left ventricular wall thickness can be measured bymethods known in the art, such as by echocardiography, CT scan, or acardiac MRI.

In some embodiments, the subject has abnormal cardiac fibrosis prior totreatment. In some embodiments, the abnormal cardiac fibrosis is reducedby greater than 5%, such as greater than 8%, 10%, 12%, 15%, 20%, or 30%following treatment. Cardiac fibrosis can be measured by methods knownin the art, such as by biopsy or a cardiac MRI.

In some embodiments, the subject has reduced exercise capacity prior totreatment. In some embodiments, the exercise capacity of the subject isincreased by greater than 5%, such as greater than 8%, 10%, 12%, 15%,20% or 30% following treatment. In some embodiments, the exercisecapacity is measured by cardiopulmonary exercise testing (CPET). CPETmeasures changes in oxygen consumption (VO₂ max). Methods of measuringCPET and VO₂ max are well known in the art (Malhotra et al., JACC: HeartFailure, 2016, 4(8): 607-616; Guazzi et al., J Amer College Cardiol,2017, 70 (13): 1618-1636; Rowin et al., JACC: Cariovasc Imaging, 2017,10(11):1374-1386). In some embodiments, VO₂ max is improved by more than1 mL/kg/m², such as more than 1.2 mL/kg/m², 1.4 mL/kg/m², 1.5 mL/kg/m²,1.7 mL/kg/m², 2 mL/kg/m², 2.2 mL/kg/m², 2.5 mL/kg/m², 3 mL/kg/m², 3.2mL/kg/m², or 3.5 mL/kg/m² following treatment.

In some embodiments, the subject has a New York Heart Association (NYHA)Functional Classification of II, III, or IV prior to treatment. In someembodiments, the subject has a New York Heart Association (NYHA)Functional Classification of III or IV prior to treatment. In someembodiments, the subject has a New York Heart Association (NYHA)Functional Classification of IV prior to treatment. In some embodiments,the subject remains in the same NYHA functional class or has a reducedNYHA functional class following treatment.

In some embodiments, VO₂ max is improved by more than 1 mL/kg/m², suchas more than 1.2 mL/kg/m², 1.4 mL/kg/m², 1.5 mL/kg/m², 1.7 mL/kg/m², or2 mL/kg/m² and the subject has a reduced NYHA functional class followingtreatment. In some embodiments, VO₂ max is improved by more than 2.5mL/kg/m², 3 mL/kg/m², 3.2 mL/kg/m², or 3.5 mL/kg/m² and the subjectremains in the same NYHA functional class or has a reduced NYHAfunctional class following treatment.

In some embodiments, daily function and/or activity level of the subjectis improved following treatment. Improved daily function and/or activitylevel may be measured, for example, by journaling or actigraphy, such asa FitBit or FitBit-like monitors.

In some embodiments, the subject has one or more of decreased shortnessof breath, decreased chest pain, decreased arrhythmia burden, such asatrial fibrillation and ventricular arrhythmias, decreased incidence ofheart failure, and decreased ventricular outflow obstruction followingtreatment.

Dosages

The compounds and compositions disclosed and/or described herein areadministered at a therapeutically effective dosage, e.g., a dosagesufficient to provide treatment for the disease state. While humandosage levels have yet to be optimized for the chemical entitiesdescribed herein, generally, a daily dose ranges from about 0.01 to 100mg/kg of body weight; in some embodiments, from about 0.05 to 10.0 mg/kgof body weight, and in some embodiments, from about 0.10 to 1.4 mg/kg ofbody weight. Thus, for administration to a 70 kg person, in someembodiments, the dosage range would be about from 0.7 to 7000 mg perday; in some embodiments, about from 3.5 to 700.0 mg per day, and insome embodiments, about from 7 to 100.0 mg per day. The amount of thechemical entity administered will be dependent, for example, on thesubject and disease state being treated, the severity of the affliction,the manner and schedule of administration and the judgment of theprescribing physician. For example, an exemplary dosage range for oraladministration is from about 5 mg to about 500 mg per day, and anexemplary intravenous administration dosage is from about 5 mg to about500 mg per day, each depending upon the compound pharmacokinetics.

A daily dose is the total amount administered in a day. A daily dose maybe, but is not limited to be, administered each day, every other day,each week, every 2 weeks, every month, or at a varied interval. In someembodiments, the daily dose is administered for a period ranging from asingle day to the life of the subject. In some embodiments, the dailydose is administered once a day. In some embodiments, the daily dose isadministered in multiple divided doses, such as in 2, 3, or 4 divideddoses. In some embodiments, the daily dose is administered in 2 divideddoses.

Administration of the compounds and compositions disclosed and/ordescribed herein can be via any accepted mode of administration fortherapeutic agents including, but not limited to, oral, sublingual,subcutaneous, parenteral, intravenous, intranasal, topical, transdermal,intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, orintraocular administration. In some embodiments, the compound orcomposition is administered orally or intravenously. In someembodiments, the compound or composition disclosed and/or describedherein is administered orally.

Pharmaceutically acceptable compositions include solid, semi-solid,liquid and aerosol dosage forms, such as tablet, capsule, powder,liquid, suspension, suppository, and aerosol forms. The compoundsdisclosed and/or described herein can also be administered in sustainedor controlled release dosage forms (e.g., controlled/sustained releasepill, depot injection, osmotic pump, or transdermal (includingelectrotransport) patch forms) for prolonged timed, and/or pulsedadministration at a predetermined rate. In some embodiments, thecompositions are provided in unit dosage forms suitable for singleadministration of a precise dose.

The compounds disclosed and/or described herein can be administeredeither alone or in combination with one or more conventionalpharmaceutical carriers or excipients (e.g., mannitol, lactose, starch,magnesium stearate, sodium saccharine, talcum, cellulose, sodiumcrosscarmellose, glucose, gelatin, sucrose, magnesium carbonate). Ifdesired, the pharmaceutical composition can also contain minor amountsof nontoxic auxiliary substances such as wetting agents, emulsifyingagents, solubilizing agents, pH buffering agents and the like (e.g.,sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitanmonolaurate, triethanolamine acetate, triethanolamine oleate).Generally, depending on the intended mode of administration, thepharmaceutical composition will contain about 0.005% to 95%, or about0.5% to 50%, by weight of a compound disclosed and/or described herein.Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa.

In some embodiments, the compositions will take the form of a pill ortablet and thus the composition may contain, along with a compoundsdisclosed and/or described herein, one or more of a diluent (e.g.,lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesiumstearate), and/or a binder (e.g., starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives). Othersolid dosage forms include a powder, marume, solution or suspension(e.g., in propylene carbonate, vegetable oils or triglycerides)encapsulated in a gelatin capsule.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing or suspending etc. a compounddisclosed and/or described herein and optional pharmaceutical additivesin a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols,ethanol or the like) to form a solution or suspension. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, as emulsions, or in solid forms suitable for dissolution orsuspension in liquid prior to injection. The percentage of the compoundcontained in such parenteral compositions depends, for example, on thephysical nature of the compound, the activity of the compound and theneeds of the subject. However, percentages of active ingredient of 0.01%to 10% in solution are employable, and may be higher if the compositionis a solid which will be subsequently diluted to another concentration.In some embodiments, the composition will comprise from about 0.2 to 2%of a compound disclosed and/or described herein in solution.

Pharmaceutical compositions of the compounds disclosed and/or describedherein may also be administered to the respiratory tract as an aerosolor solution for a nebulizer, or as a microfine powder for insufflation,alone or in combination with an inert carrier such as lactose. In such acase, the particles of the pharmaceutical composition may have diametersof less than 50 microns, or in some embodiments, less than 10 microns.

In addition, pharmaceutical compositions can include a compounddisclosed and/or described herein and one or more additional medicinalagents, pharmaceutical agents, adjuvants, and the like. Suitablemedicinal and pharmaceutical agents include those described herein.

Kits

Also provided are articles of manufacture and kits containing any of thecompounds or pharmaceutical compositions provided herein. The article ofmanufacture may comprise a container with a label. Suitable containersinclude, for example, bottles, vials, and test tubes. The containers maybe formed from a variety of materials such as glass or plastic. Thecontainer may hold a pharmaceutical composition provided herein. Thelabel on the container may indicate that the pharmaceutical compositionis used for preventing, treating or suppressing a condition describedherein, and may also indicate directions for either in vivo or in vitrouse.

In one aspect, provided herein are kits containing a compound orcomposition described herein and instructions for use. The kits maycontain instructions for use in the treatment of a heart disease in anindividual or subject in need thereof. A kit may additionally containany materials or equipment that may be used in the administration of thecompound or composition, such as vials, syringes, or IV bags. A kit mayalso contain sterile packaging.

Combinations

The compounds and compositions described and/or disclosed herein may beadministered alone or in combination with other therapies and/ortherapeutic agents useful in the treatment of the aforementioneddisorders, diseases, or conditions.

The compounds and compositions described and/or disclosed herein may becombined with one or more other therapies to treat a heart disease, suchas HCM or HFpEF. In some embodiments, the one or more therapies includetherapies that retard the progression of heart failure bydown-regulating neurohormonal stimulation of the heart and attempt toprevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptorblockers (ARBs), β-blockers, aldosterone receptor antagonists, or neuralendopeptidase inhibitors). In some embodiments, the one or moretherapies include therapies that improve cardiac function by stimulatingcardiac contractility (e.g., positive inotropic agents, such as theβ-adrenergic agonist dobutamine or the phosphodiesterase inhibitormilrinone). In other embodiments, the one or more therapies includetherapies that reduce cardiac preload (e.g., diuretics, such asfurosemide) or afterload (vasodilators of any class, including but notlimited to calcium channel blockers, phosphodiesterase inhibitors,endothelin receptor antagonists, renin inhibitors, or smooth musclemyosin modulators).

The compounds and compositions described and/or disclosed herein may becombined with one or more other therapies to treat HCM or HFpEF. In someembodiments, the compounds and/compositions may be combined with aβ-blocker, verapamil, and/or disopyramide.

General Synthetic Methods

Compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2) willnow be described by reference to illustrative synthetic schemes fortheir general preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. In addition, one of skill in the art will recognizethat protecting groups may be used to protect certain functional groups(amino, carboxy, or side chain groups) from reaction conditions, andthat such groups are removed under standard conditions when appropriate.Unless otherwise specified, the variables are as defined above inreference to Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and (In-2).

Where it is desired to obtain a particular enantiomer of a compound,this may be accomplished from a corresponding mixture of enantiomersusing any suitable conventional procedure for separating or resolvingenantiomers. Thus, for example, diastereomeric derivatives may beproduced by reaction of a mixture of enantiomers, e.g. a racemate, andan appropriate chiral compound. The diastereomers may then be separatedby any convenient means, for example by crystallization and the desiredenantiomer recovered. In another resolution process, a racemate may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

General methods of preparing compounds described herein are depicted inexemplified methods below. Variable groups in the schemes providedherein are defined as for Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1), and(In-2), or any variation thereof. Other compounds described herein maybe prepared by similar methods.

In some embodiments, compounds provided herein may be synthesizedaccording to Scheme 1.

wherein R¹, R^(2A), R^(2B), R³, R⁴, and R⁵ are as defined for formula(I), or any variation thereof detailed herein.

An exemplary embodiment of the preparative method in Scheme 1 is shownin Scheme 1a.

wherein R^(2A) and R^(2B) are as defined for formula (I), or anyvariation thereof detailed herein; and wherein R^(1a) is as defined forformula (If), or any variation thereof detailed herein.

Another exemplary embodiment of the preparative method in Scheme 1 isshown in Scheme 1b.

wherein R¹, R³, R⁴, and R⁵ are as defined for formula (I), or anyvariation thereof detailed herein, and wherein R^(2a) is as defined forformula (If), or any variation thereof detailed herein.

Another exemplary embodiment of the preparative method in Scheme 1 isshown in Scheme 1c.

wherein R^(1a) and R^(2a) are as defined for formula (If), or anyvariation thereof detailed herein.

In some embodiments, compounds provided herein may be synthesizedaccording to Scheme 2.

wherein R¹, R^(2A), R^(2B), R³, R⁴, and R⁵ are as defined for formula(I), or any variation thereof detailed herein.

Another exemplary embodiment of the preparative method in Scheme 2 isshown in Scheme 2a.

wherein R^(2A) and R^(2B) are as defined for formula (I), or anyvariation thereof detailed herein; and wherein R^(1a) is as defined forformula (If), or any variation thereof detailed herein.

Another exemplary embodiment of the preparative method in Scheme 2 isshown in Scheme 2b.

wherein R¹, R³, R⁴, and R⁵ are as defined for formula (I), or anyvariation thereof detailed herein, wherein R^(2a) is as defined forformula (If), or any variation thereof detailed herein, and wherein X ishalogen.

Another exemplary embodiment (e.g., of the preparative method in Scheme2) is shown in Scheme 2c.

wherein R¹, R³, R⁴, and R⁵ are as defined for formula (I), or anyvariation thereof detailed herein.

Another exemplary embodiment of the preparative method in Scheme 2 isshown in Scheme 2d.

wherein R^(1a) and R^(2a) are as defined for formula (If), or anyvariation thereof detailed herein.

Another exemplary embodiment (e.g., of the preparative method in Scheme2) is shown in Scheme 2e.

Another exemplary embodiment (e.g., of the preparative method in Scheme2) is shown in Scheme 2f

Another exemplary embodiment of the preparative method in Scheme 2 isshown in Scheme 2g.

wherein X is halide; wherein R^(2A) and R³ are as defined for formula(I), or any variation thereof detailed herein; and wherein R^(1a) and mare as defined for formula (Ik-1), or any variation thereof detailedherein.

In some embodiments, compounds provided herein may be synthesizedaccording to Scheme 3.

wherein R¹, R^(2A), R^(2B), R³, R⁴, and R⁵ are as defined for formula(I), or any variation thereof detailed herein.

Another exemplary embodiment of the preparative method in Scheme 3 isshown in Scheme 3a.

wherein R^(1a) is as defined for formula (If), or any variation thereofdetailed herein; and wherein R^(a) and Rb are independently H or C₁-C₆alkyl.

Another exemplary embodiment of the preparative method in Scheme 3 isshown in Scheme 3b-1.

wherein X is CH or N; and wherein R^(1a) is as defined for formula (If),or any variation thereof detailed herein.

Another exemplary embodiment of the preparative method in Scheme 3 isshown in Scheme 3b-2.

wherein X is CH or N; and wherein R^(1a) is as defined for formula (If),or any variation thereof detailed herein.

Another exemplary embodiment of the preparative method in Scheme 3 isshown in Scheme 3c.

wherein R^(1a) is as defined for formula (If), or any variation thereofdetailed herein.

Another exemplary embodiment of the preparative method in Scheme 3 isshown in Scheme 3d.

wherein R^(2A) is as defined for formula (I), or any variation thereofdetailed herein; and wherein R^(1a) is selected from the groupconsisting of cyano, halo, substituted or unsubstituted alkoxy,substituted or unsubstituted alkyl, and substituted or unsubstitutedheterocyclyl.

Another exemplary embodiment of the preparative method in Scheme 3 isshown in Scheme 3e.

wherein R^(1a) is selected from the group consisting of cyano, halo,substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl,and substituted or unsubstituted heterocyclyl.

Another exemplary embodiment of the preparative method in Scheme 3 isshown in Scheme 3f

wherein R^(1a) is selected from the group consisting of halo andsubstituted or unsubstituted alkyl; and wherein m is 0, 1, or 2.

Another exemplary embodiment of the preparative method in Scheme 3 isshown in Scheme 3g.

wherein R^(1a) and m are as defined for formula (Ik-1), or any variationthereof detailed herein.

Another exemplary preparative method is shown in Scheme 4.

wherein R^(1a), R^(3a), m, and p are as defined for formula (Ik-1), orany variation thereof detailed herein.

Particular non-limiting examples are provided in the Example sectionbelow.

EXAMPLES

The following examples are offered to illustrate but not to limit thecompositions, uses, and methods provided herein. The compounds areprepared using the general methods described above. In the followingexamples, designation of a compound by use of a compound number followedby a particular letter indicates a stereoisomeric form or mixture ofstereoisomers of such compound, as will be clear from the context of theparticular example. Thus, it will be appreciated that if a compound suchas Compound 288 may exist as two individual stereoisomeric forms, twoletter designations, 288A and 288B, may be used herein to refer to theindividual stereoisomeric forms. Similarly, individual diastereomers ormixtures thereof, as will be clear from the examples below, may bedesignated as 858A, 858B, 858C, and 858D. It is appreciated that thedata tables presented herein, for example Table A, where applicable,will provide the data associated with a particular stereoisomer by usingthe designations indicated in these examples. By virtue of theterminology used herein, it is also appreciated that certain compoundsreferred to in a particular stereoisomeric form in these examples withthe letter designation may find counterparts in Table 1 where suchcompounds are indicated by structure and name.

The following abbreviations are used throughout the Examples: TEA(trimethylamine), DCM (dichloromethane), (Boc)₂O (di-tert-butyldecarbonate), EA (Ethyl acetate), PE (Petroleum ether, DMF(N,N-dimethylformamide), DIEA (N-ethyl-N-isopropylpropan-2-amine), HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate), HOAt (1-Hydroxy-7-azabenzotriazole), HOBt(Hydroxybenzotriazole), EDCI(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), MeOH (methanol), EtOH(ethanol), IPA (iPrOH; propan-2-ol), NMP (1-methylpyrrolidin-2-one),STAB (sodium triacetoxyhydroborate), ACN (acetonitrile), TFA(trifluoroacetic acid), DPPA (Diphenylphosphoryl azide), DBU(1,8-Diazabicyclo(5.4.0)undec-7-ene), THF (tetrahydrofuran), PPh₃(triphenylphosphane), SM (starting material), Hex (hexane), NCS(N-chlorosuccinimide), r.t. (room temperature), DCE (dichloroethane), FA(formic acid), CHCl₃ (Chloroform), BnBr (benzyl bromide), HCl (hydrogenchloride), equiv (equivalent), RT (retention time), SFC (supercriticalfluid chromatography), and DSC (bis(2,5-dioxopyrrolidin-1-yl)carbonate).

Example 1: Synthesis of Compound 288 1. Synthesis of Intermediate 1-2

To a solution of methyl 2-amino-2-(4-chlorophenyl)acetate (1.5 g, 7.51mmol, 1.0 equiv) in DCE (20 mL) at r.t were added 4-chlorobenzaldehyde(1.05 g, 7.47 mmol, 1.00 equiv), acetic acid (900 mg, 14.99 mmol, 2.00equiv) and STAB (2.4 g, 11.32 mmol, 1.50 equiv). The mixture was stirredat r.t for 2 h, diluted with EA (100 mL), washed with brine (50 mL)twice, dried over anhydrous sodium sulfate and concentrated underreduced pressure to give 2.4 g (99%) of methyl2-(4-chlorophenyl)-2-[[(4-chlorophenyl)methyl]amino]acetate as a brownoil.

2. Synthesis of Intermediate 1-3

To a solution of methyl2-(4-chlorophenyl)-2-[[(4-chlorophenyl)methyl]amino]acetate (2.4 g, 7.40mmol, 1.00 equiv) in DCM (30 mL) at r.t were added TEA (1.5 g, 14.82mmol, 2.00 equiv) and 2-chloroacetyl chloride (1 g, 8.85 mmol, 1.20equiv) dropwise. The mixture was stirred at r.t for 2 h, diluted withDCM (50 mL), washed with brine (20 mL) twice, dried over anhydroussodium sulfate, concentrated under reduced pressure, and purified bysilica gel column with ACN and water (3:1) to give 2 g (67%) of methyl2-[2-chloro-N-[(4-chlorophenyl)methyl]acetamido]-2-(4-chlorophenyl)acetateas a brown oil.

3. Synthesis of Compound 288

To a solution of methyl2-[2-chloro-N-[(4-chlorophenyl)methyl]acetamido]-2-(4-chlorophenyl)acetate(150 mg, 0.37 mmol, 1.0 equiv) in ACN (10 mL) at r.t were addedpropan-2-amine (66.5 mg, 1.1 mmol, 3.0 equiv) and TEA (115 mg, 1.1 mmol,3.0 equiv). The mixture was stirred at r.t for 1 h and at 80° C. for 2h, concentrated under reduced pressure, and purified by Prep-HPLC withthe following conditions (2 #-AnalyseHPLC-SHIMADZU (HPLC-10)): Column,XBridge Shield RP18 OBD column, 5 um, 19*150 mm; mobile phase, water(0.05% NH₃H₂O) and ACN (48.0% ACN up to 68.0% in 8 min); Detector, UV220 nm) to give 100 mg of3-(4-chlorophenyl)-4-[(4-chlorophenyl)methyl]-1-(propan-2-yl)piperazine-2,5-dione.LRMS (ES) m/z 391 (M+H). ¹H NMR (DMSO-d₆, 300 MHz) δ 7.44-7.33 (m, 2H),7.36-7.22 (m, 4H), 7.22-7.13 (m, 2H), 4.95 (s, 1H), 4.88 (d, J=15.1 Hz,1H), 4.40 (h, J=6.9 Hz, 1H), 4.15 (d, J=17.7 Hz, 1H), 3.98 (d, J=17.8Hz, 1H), 3.86 (d, J=15.1 Hz, 1H), 1.07 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.8Hz, 3H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 288:

Compound No. LRMS (ES) m/z 293 M + H = 392 294 M + H = 357 297 M + H =392 298 M + H = 391 299 M + H = 375 300 M + H = 371 301 M + H = 382 302M + H = 391 303 M + H = 375 304 M + H = 371 305 M + H = 371 306 M + H =382 307 M + H = 382 308 M + H = 425 309 M + H = 425 310 M + H = 391 311M + H = 375 312 M + H = 391 313 M + H = 387 314 M + H = 425 315 M + H =426 316 M + H = 405 317 M + H = 383 318 M + H = 397.2 319 M + H = 417.1

4. Separation of Compound 288 Enantiomers: Enantiomers 288A and 288B

The racemic compound 3-(4-chlorophenyl)-4-[(4-chlorophenyl)methyl]-1-cyclopentylpiperazine-2, 5-dione (80 mg, 0.19 mmol, 1.0 equiv)was separated by Chiral-HPLC with the following conditions (Column:CHIRAL ART Cellulose-SB, 2*25 cm, 5 um; Mobile Phase A: Hex-HPLC, MobilePhase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 30 B to 30 B in 10min; 220/254 nm) to give 25.4 mg (first eluted peak) of Enantiomer 288Aand 32 mg (second eluted peak) of Enantiomer 288B. The chiral analyticaldata (Column: CHIRAL Cellulose-SB; 0.46 cm×15 cm; 5 micron; Hex (0.2%IPAmine):EtOH=70:30 at 1 ml/min) shows that Enantiomer 288A is the firsteluting peak (RT 3.3 min) and Enantiomer 288B is the second eluting peak(RT 4.0 min).

Enantiomer 288A: LRMS (ES) m/z 391 (M+H). ¹H NMR (300 MHz, DMSO-d₆) δ7.44-7.34 (m, 2H), 7.39-7.22 (m, 4H), 7.27-7.13 (m, 2H), 4.95 (s, 1H),4.87 (d, J=15.1 Hz, 1H), 4.39 (h, J=6.8 Hz, 1H), 4.15 (d, J=17.7 Hz,1H), 3.97 (d, J=17.8 Hz, 1H), 3.86 (d, J=15.1 Hz, 1H), 1.07 (d, J=6.8Hz, 3H), 0.96 (d, J=6.9 Hz, 3H).

Enantiomer 288B: LRMS (ES) m/z 391 (M+H). ¹H NMR (300 MHz, DMSO-d₆) δ7.44-7.33 (m, 2H), 7.36-7.22 (m, 4H), 7.22-7.13 (m, 2H), 4.95 (s, 1H),4.87 (d, J=15.1 Hz, 1H), 4.41 (p, J=6.8 Hz, 1H), 4.15 (d, J=17.7 Hz,1H), 3.97 (d, J=17.8 Hz, 1H), 3.86 (d, J=15.1 Hz, 1H), 1.07 (d, J=6.8Hz, 3H), 0.96 (d, J=6.9 Hz, 3H).

The following compounds were prepared by methods analogous to the methoddescribed for Enantiomers 288A and 288B:

HPLC Enantiomer RT LRMS (ES) HPLC separation No. (min) m/z conditions293A 2.1 M + H = 392 CHIRALPAK IA-3; 293B 2.5 M + H = 392 0.46 cm × 5cm; 3 micro; 297A 1.7 M + H = 392 Hex(0.1% DEA):EtOH = 50:50 297B 2.3M + H = 392 at 1 mL/min 629A 1.48 M + H = 473 CHIRALPAK IE-3; 0.46 cm ×5 cm; 3 micro; 629B 1.90 M + H = 473 Hex(0.1% DEA):EtOH = 50:50 at 1ml/min

Example 2: Synthesis of Compound 20

To a solution of5-(4-chlorobenzyl)-2-(4-fluorophenyl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione(20.5 mg, 0.049 mmol, 1.0 equiv) in dry THF (2 mL) at −78° C. was addedLHMDS (1 M in THF, 54 μL, 0.054 mmol, 1.1 equiv). The mixture wasstirred at −78° C. for 2 min, added MeI (2 M in ether, 30 μL, 0.059mmol, 1.2 equiv) into the mixture, stirred at −78° C. for 5 min, slowlywarmed to r.t., and diluted with water and EA. The organic layer wasdried over Na₂SO₄, filtered, concentrated, and purified by silica gelchromatography (40 g column, 0-60% EtOAc in hexanes) to provide 9.9 mg(47%) of5-(4-chlorobenzyl)-2-(4-fluorophenyl)-8-isopropyl-7-methyl-2,5,8-triazaspiro[3.5]nonane-6,9-dioneas a white solid. LRMS (ES) m/z 430.1 (M+H). (Methylenechloride-d₂, 400MHz, ppm) δ 7.40-7.28 (m, 2H), 7.24-7.13 (m, 2H), 7.06-6.91 (m, 2H),6.46-6.37 (m, 2H), 5.29 (d, J=16.2 Hz, 1H), 4.87 (d, J=16.3 Hz, 1H),4.72 (d, J=8.6 Hz, 1H), 4.44 (hept, J=6.8 Hz, 1H), 4.28-4.14 (m, 2H),4.03 (dd, J=9.8, 8.2 Hz, 2H), 1.49 (d, J=7.0 Hz, 3H), 1.33 (dd, J=6.9,5.0 Hz, 6H).

The following compound was prepared by methods analogous to the methoddescribed for Compound 20:

Compound No. LRMS (ES) m/z 329 M + H = 412.1

Example 3: Synthesis of Compound 65 1. Synthesis of Intermediate 3-2

To a solution of 1-(tert-butyl)3-methyl-3-aminoazetidine-1,3-dicarboxylate (5.0 g, 21.7 mmol, 1.0equiv) in MeOH (50 mL) was added 4-chlorobenzaldehyde (4.5 g, 32.6 mmol,1.5 equiv). The mixture was stirred for 1 h at r.t. To this mixture wereadded NaCNBH₃ (1.4 g, 21.7 mmol, 1.0 equiv) and AcOH (1 mL). Thismixture was continued to be stirred for 4 h, concentrated under reducedpressure, and diluted with DCM (60 mL) and saturated aqueous sodiumbicarbonate (60 mL). The aqueous layer was extracted with DCM (25 mL).The combined organic layers were dried over sodium sulfate, filteredthrough celite, concentrated under reduced pressure, and purified bysilica gel chromatography (80 g column, 0-100% EtOAc in hexanes) toprovide 6.0 g (78%) of 1-(tert-butyl) 3-methyl3-((4-chlorobenzyl)amino)azetidine-1,3-dicarboxylate. LRMS (ES) m/z355.2 (M+H). ¹H-NMR (Methylenechloride-d₂, 400 MHz, ppm) δ 7.35 (s, 4H),4.19 (d, J=8.8 Hz, 2H), 3.86 (d, J=8.8 Hz, 2H), 3.82 (s, 3H), 3.68 (s,2H), 1.46 (s, 9H).

2. Synthesis of Intermediate 3-3

To a solution of 1-(tert-butyl) 3-methyl3-((4-chlorobenzyl)amino)azetidine-1,3-dicarboxylate (6.0 g, 16.9 mmol,1.0 equiv) in DCM (50 mL) cooled down to 0° C. were added TEA (7.1 mL,50.7 mmol, 3.0 equiv) and chloroacetyl chloride (2.7 mL, 33.8 mmol, 2.0equiv). The ice bath was removed and the mixture was stirred for 3 h atr.t. before pouring into saturated aqueous NH₄Cl (200 mL). The aqueouslayer was extracted with DCM (100 mL) three times. The combined organiclayers were dried over MgSO₄ and concentrated to give an intermediateproduct, 1-(tert-butyl) 3-methyl3-(2-chloro-N-(4-chlorobenzyl)acetamido)azetidine-1,3-dicarboxylate.LRMS (ES) m/z 431.1 (M+H).

3. Synthesis of Intermediate 3-4

To a solution of 1-(tert-butyl) 3-methyl3-(2-chloro-N-(4-chlorobenzyl)acetamido)azetidine-1,3-dicarboxylate(16.9 mmol, 1.0 equiv assuming 100% yield) in ACN (300 mL) were addedisopropylamine (2.9 mL, 33.9 mmol, 2.0 equiv) and TEA (7.1 mL, 50.8mmol, 3.0 equiv). The mixture was heated to 80° C. for 15 h,concentrated, and purified by silica gel chromatography (80 g, 0-100%EtOAc in hexanes) to provide 6.5 g (91%) of tert-butyl5-(4-chlorobenzyl)-8-isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylateas a colored solid. LRMS (ES) m/z 366.1 (M+H-^(t)Bu).

4. Synthesis of Intermediate 3-5

To a solution of tert-butyl5-(4-chlorobenzyl)-8-isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(6.5 g, 15.4 mmol, 1.0 equiv) in DCM (40 mL) was added TFA (12 mL). Themixture was stirred for 1 h at r.t, concentrated, diluted with saturatedaqueous NaHCO₃ (200 mL), and extracted with DCM three times. Thecombined organic layers were dried over MgSO₄, concentrated, andpurified by silica gel chromatography (40 g column, 0-50% MeOH in DCM)to provide 4.1 g (83%) of5-(4-chlorobenzyl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione asan off-white solid. LRMS (ES) m/z 322.1 (M+H). ¹H-NMR(Dichloromethane-d₂, 400 MHz, ppm) δ 7.36-7.32 (m, 2H), 7.28-7.24 (m,2H), 5.16 (s, 2H), 4.85 (p, J=6.9 Hz, 1H), 4.30-4.19 (m, 4H), 4.00 (s,2H), 1.24 (d, J=6.8 Hz, 6H).

5. Synthesis of Compound 65

To a solution of5-(4-chlorobenzyl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione(20 mg, 0.062 mmol, 1.0 equiv) in DCM (0.2 mL) were added DIEA (22 μL,0.12 mmol, 2.0 equiv) and methyl isocyanate (5.0 mg, 0.093 mmol, 1.5equiv). The mixture was stirred for 15 h at r.t., concentrated, andpurified by reverse phase HPLC (Phenomenex, gemini 5 micron C18 150×21.2mm, 10-70% acetonitrile in water both with 0.1% formic acid gradientover 25 min) to provide 8.6 mg (37%) of5-(4-chlorobenzyl)-8-isopropyl-N-methyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carboxamideas a white foamy solid. LRMS (ES) m/z 379.1 (M+H). (Methanol-d₄, 400MHz, ppm) δ 7.39-7.34 (m, 2H), 7.32-7.27 (m, 2H), 4.98 (s, 2H), 4.75(hept, J=6.9 Hz, 1H), 4.41-4.37 (m, 2H), 4.08 (s, 2H), 4.07-4.04 (m,2H), 2.69 (s, 3H), 1.24 (d, J=6.8 Hz, 6H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 65:

Compound No. LRMS (ES) m/z 64 M + H = 380.1 66 M + H = 445.2 67 M + H =413.1 68 M + H = 399.1 69 M + H = 384.1 70 M + H = 439.2

Example 4: Synthesis of Compound 373 1. Synthesis of Intermediate 4-2

To a solution of 1-tert-butyl 3-methyl3-aminopyrrolidine-1,3-dicarboxylate (1.9 g, 7.78 mmol, 1.0 equiv) inDCE (30 mL) at r.t were added 4-chlorobenzaldehyde (1.1 g, 7.83 mmol,1.0 equiv) and acetic acid (934 mg, 15.55 mmol, 2.0 equiv). The mixturewas stirred for 10 min at r.t. To this mixture was added STAB (2.5 g,11.80 mmol, 1.50 equiv) in portions. The mixture was continued to stirfor 1.5 h, quenched with water (20 mL), and extracted with DCM (20 mL)twice. The combined organic layers were washed with aqueous NaHCO₃ (20mL) and brine (20 mL), dried over anhydrous sodium sulfate, concentratedunder reduced pressure, and purified by reverse phase HPLC with thefollowing conditions: (column, C18 silica gel; mobile phase, A: water(10 mmol/L NH₄HCO₃), B: ACN, 65% B to 75% B gradient in 20 min;detector, UV 210/254 nm) to give 2.2 g (77%) of 1-tert-butyl 3-methyl3-[[(4-chlorophenyl)methyl]amino]pyrrolidine-1,3-dicarboxylate as abrown oil. LRMS (ES) m/z 313 (M+H-56).

2. Synthesis of Intermediate 4-3

To a solution of 1-tert-butyl 3-methyl3-[[(4-chlorophenyl)methyl]amino]pyrrolidine-1,3-dicarboxylate (2.28 g,6.18 mmol, 1.0 equiv) in DCM (30 mL) cooled to 0° C. were added2-chloroacetyl chloride (3.12 g, 27.62 mmol, 4.50 equiv) and TEA (5.63g, 55.64 mmol, 9.00 equiv). The mixture was stirred overnight at r.t.,quenched with water (20 mL), and extracted with DCM (20 mL) twice. Thecombined organic layers were washed with brine (20 mL) twice, dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive 2.9 g of 1-tert-butyl 3-methyl3-[2-chloro-N-[(4-chlorophenyl)methyl]acetamido]pyrrolidine-1,3-dicarboxylateas a brown oil. LRMS (ES) m/z 389 (M+H-56).

3. Synthesis of Intermediate 4-4

To a solution of 1-tert-butyl 3-methyl3-[2-chloro-N-[(4-chlorophenyl)methyl]acetamido]pyrrolidine-1,3-dicarboxylate(2.9 g, 6.51 mmol, 1.0 equiv) in ACN (30 mL) at r.t were addedpropan-2-amine (1.9 g, 32.14 mmol, 5.00 equiv) and TEA (5.3 g, 8.00equiv). The mixture was stirred for 1 h at r.t and then heated to 80° C.overnight. The following day the mixture was cooled to r.t, concentratedunder reduced pressure, and purified by reverse phase HPLC with thefollowing conditions: column, C18 silica gel; mobile phase, A: water (10mmol/L NH₄HCO₃), B: ACN, 20% B to 25% B gradient in 20 min; detector, UV210/254 nm to give 2.4 g (85%) of tert-butyl6-[(4-chlorophenyl)methyl]-7,10-dioxo-9-(propan-2-yl)-2,6,9-triazaspiro[4.5]decane-2-carboxylateas a brown solid. LRMS (ES) m/z 380 (M+H-56).

4. Synthesis of Intermediate 4-5

To a solution of tert-butyl6-[(4-chlorophenyl)methyl]-7,10-dioxo-9-(propan-2-yl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate(2.4 g, 5.51 mmol, 1.0 equiv) in DCM (30 mL) at r.t was added TFA (8mL). The mixture was stirred for 1 h at r.t. The pH of the solution wasadjusted to 9 with sodium hydroxide (6 N, ˜3 mL). The mixture wasdiluted with water and extracted with DCM (20 mL) twice. The combinedorganic layers were washed with brine (20 mL) twice, dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive 1.7 g (92%) of6-[(4-chlorophenyl)methyl]-9-(propan-2-yl)-2,6,9-triazaspiro[4.5]decane-7,10-dioneas a brown solid. LRMS (ES) m/z 336 (M+H).

5. Synthesis of Compound 373

To a solution of 2-bromopyridine (200 mg, 1.27 mmol, 1.0 equiv) indioxane (5 mL) were added6-[(4-chlorophenyl)methyl]-9-(propan-2-yl)-2,6,9-triazaspiro[4.5]decane-7,10-dione(94 mg, 0.28 mmol, 1.0 equiv), Pd₂(dba)₃CHCl₃ (62 mg, 0.06 mmol, 0.10equiv), Xphos (57 mg, 0.12 mmol 0.20 equiv), and Cs₂CO₃ (389 mg, 1.19mmol, 2.0 equiv) under nitrogen. The mixture was stirred at 90° C.overnight, cooled to r.t, filtered to remove solids, and purified byPrep-HPLC with the following conditions (2 #-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobilephase, water (10 mmol/L NH₄HCO₃) and ACN (39.0% ACN up to 53.0% gradientover 8 min); Detector, UV 254 nm to give 15 mg (6%) of6-[(4-chlorophenyl)methyl]-9-(propan-2-yl)-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane-7,10-dioneas a white solid. LRMS (ES) m/z 413 (M+H). ¹H-NMR: (300 MHz,Methanol-d₄, ppm): δ 8.01-7.93 (m, 1H), 7.50 (ddd, J=8.9, 7.2, 1.9 Hz,1H), 7.28-7.19 (m, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.61 (dd, J=6.9, 5.2 Hz,1H), 6.41 (d, J=8.6 Hz, 1H), 4.76-4.54 (m, 3H), 4.16 (s, 2H), 3.97 (d,J=11.9 Hz, 1H), 3.75 (d, J=11.8 Hz, 1H), 3.66-3.42 (m, 2H), 2.62-2.38(m, 2H), 1.20 (dd, J=6.8, 1.4 Hz, 6H).

6. Separation of Compound 373 Enantiomers

The racemic compound6-[(4-chlorophenyl)methyl]-9-(propan-2-yl)-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane-7,10-dione(80 mg, 0.19 mmol, 1.0 equiv) was separated by Chiral-HPLC with thefollowing conditions (Prep-HPLC-009): Column: Chiralpak IC, 2*25 cm, 5um; Mobile Phase A: Hex-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 15mL/min; isocratic elution for 21 min; 220/254 nm) to give 28.7 mg (36%,first eluted peak) of Enantiomer 373A and 29 mg (second eluted peak) ofEnantiomer 373B as white solids. The chiral analytical data (CHIRALPAKIC-3; 0.46 cm×5 cm; 3 μm; Hex (0.1% DEA):EtOH=55:45 at 1 ml/min) showsthat Enantiomer 373A is the first eluted peak (RT 2.2 min) andEnantiomer 373B is the second eluted peak (RT 3.2 min). Enantiomer 373A:LRMS (ES) m/z 413 (M+H). ¹H-NMR: (300 MHz, Methanol-d₄, ppm) δ 7.97(ddd, J=5.2, 1.9, 0.9 Hz, 1H), 7.50 (ddd, J=8.8, 7.1, 1.9 Hz, 1H),7.28-7.18 (m, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.61 (ddd, J=7.2, 5.1, 0.9Hz, 1H), 6.41 (d, J=8.6 Hz, 1H), 4.86 (s, 1H), 4.76-4.54 (m, 2H), 4.15(s, 2H), 3.97 (d, J=11.8 Hz, 1H), 3.75 (d, J=11.8 Hz, 1H), 3.66-3.42 (m,2H), 2.62-2.38 (m, 2H), 1.20 (dd, J=6.8, 1.4 Hz, 6H).

Enantiomer 373B: LRMS (ES) m/z 413 (M+H). ¹H NMR: (300 MHz, Methanol-d₄)δ 8.01-7.93 (m, 1H), 7.50 (ddd, J=8.8, 7.2, 1.9 Hz, 1H), 7.28-7.18 (m,2H), 7.10 (d, J=8.3 Hz, 2H), 6.61 (dd, J=6.9, 5.4 Hz, 1H), 6.41 (d,J=8.5 Hz, 1H), 4.76-4.54 (m, 2H), 4.16 (s, 2H), 3.97 (d, J=11.8 Hz, 1H),3.75 (d, J=11.8 Hz, 1H), 3.66-3.42 (m, 2H), 2.62-2.38 (m, 2H), 1.20 (dd,J=6.9, 1.4 Hz, 6H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 373:

HPLC Separation Conditions Letter HPLC Conditions A Repaired Chiral IA;0.46 cm × 10 cm; 5 micro; Hex:EtOH = 50:50 at 1 ml/min B Repaired IA;0.46 cm × 10 cm; 5 micro; (Hex:DCM = 3:1)(0.1% DEA):EtOH = 50:50 at 1ml/min C CHIRALPAK IA-3; 0.46 cm × 5 cm; 3 micro; Hex(0.1% DEA):EtOH =50:50 at 1 ml/min D CHIRALPAK IC-3; 0.46 cm × 5 cm; 3 micro; Hex(0.1%DEA):EtOH = 55:45 at 1 ml/min E CHIRALPAK IC-3; 0.46 cm × 5 cm; 3 micro;Hex(0.1% DEA):EtOH = 50:50 at 1 ml/min F CHIRALPAK IC-3; 0.46 cm × 5 cm;3 micro; Hex(0.1% DEA):EtOH = 70:30 at 1 ml/min G CHIRALARTCellulose-SB; 0.46 cm × 10 cm; 3 micro; Hex(0.1% DEA):EtOH = 50:50 at 1ml/min H CHIRALPAK IE-3; 0.46 cm × 10 cm; 3 micro; (Hex:DCM = 3:1)(0.1%DEA):EtOH = 50:50 at 1 ml/min Enantiomer LRMS (ES) Retention HPLCSeparation No. m/z Time (min) Conditions 375A M + H = 412 3.4 A 375B M +H = 412 4.1 377A M + H = 427 2.9 D 377B M + H = 427 3.7 351A M + H = 4143.0 C 351B M + H = 414 4.9 353A M + H = 414 3.8 C 353B M + H = 414 5.0355A M + H = 427 2.0 E 355B M + H = 427 4.0 357A M + H = 431 1.7 D 357BM + H = 431 2.3 359A M + H = 414 2.6 C 359B M + H = 414 3.9 361A M + H =443 3.8 B 361B M + H = 443 5.5 363A M + H = 429 2.6 C 363B M + H = 4293.6 365A M + H = 416 2.4 B 365B M + H = 416 3.8 379A M + H = 393 2.4 E379B M + H = 393 2.9 381A M + H = 407 2.1 E 381B M + H = 407 2.5 383AM + H = 421 3.0 F 383B M + H = 421 3.6 369A M + H = 419 2.7 D 369B M + H= 419 3.4 371A M + H = 455 2.8 G 371B M + H = 455 3.7 385A M + H = 4561.6 E 385B M + H = 456 3.1 387A M + H = 437 3.3 H 387B M + H = 437 4.8

Example 5: Synthesis of Compound 108 1. Synthesis of Intermediate 5-2

To a solution of 3-amino-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylicacid (7.0 g, 30.4 mmol, 1.0 equiv) in MeOH (80 mL) was added4-(trifluoromethyl)benzaldehyde (5.6 g, 31.9 mmol, 1.05 equiv). Themixture was stirred for 1 h at r.t., added NaCNBH₃ (2.9 g, 45.6 mmol,1.5 equiv) and AcOH (0.5 mL), and stirred for 2 h. The mixturecontaining1-(tert-butoxycarbonyl)-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylicacid was used directly in the next step. LRMS (ES) m/z 389.2 (M+H).

2. Synthesis of Intermediate 5-3

To the solution containing1-(tert-butoxycarbonyl)-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylic acid (30.4 mmol, 1.0 equiv) obtained fromthe previous reaction were added DCM (100 mL) and(trimethylsilyl)diazomethane (2 M in hexanes, 45.6 mL, 91.1 mmol, 3.0equiv). The mixture was stirred for 3 h at r.t., added AcOH (5.0 g),concentrated onto silica (30 g), and purified by silica gelchromatography (120 g, 0-100% EtOAc in hexanes) to provide 7.4 g (61%over steps) of 1-(tert-butyl) 3-methyl3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-1,3-dicarboxylate as awhite solid. LRMS (ES) m/z 403.2 (M+H).

3. Synthesis of Intermediate 5-4

To a solution of 1-(tert-butyl) 3-methyl3-((4-(trifluoromethyl)benzyl)amino) pyrrolidine-1,3-dicarboxylate (7.4g, 18.4 mmol, 1.0 equiv) in DCM (50 mL) cooled to 0° C. were added TEA(7.7 mL, 84.9 mmol, 3.0 equiv) and chloroacetyl chloride (2.9 mL, 36.8mmol, 2.0 equiv). The ice bath was removed and the mixture was stirredfor 3 h at r.t before pouring into saturated aqueous NH₄Cl (200 mL). Theaqueous layer was extracted with DCM (100 mL) three times. The combinedorganic layers were dried over MgSO₄ and concentrated to give anintermediate product, 1-(tert-butyl) 3-methyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine-1,3-dicarboxylate. LRMS (ES) m/z 379.1 (M+H-Boc).

4. Synthesis of Intermediate 5-5

To a solution of 1-(tert-butyl) 3-methyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine-1,3-dicarboxylate(18.4 mmol, 1.0 equiv assuming 100% yield) in ACN (300 mL) were addedisopropylamine (4.7 mL, 55.1 mmol, 3.0 equiv) and TEA (7.7 mL, 55.1mmol, 3.0 equiv). The mixture was heated at 80° C. for 15 h,concentrated, and purified by silica gel chromatography (80 g, 0-100%EtOAc in hexanes) to provide an intermediate mixture containingtert-butyl9-isopropyl-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate.LRMS (ES) m/z 414.2 (M+H-^(t)Bu).

5. Synthesis of Intermediate 5-6

To a solution of tert-butyl9-isopropyl-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate(18.4 mmol, 1.0 equiv) in DCM (40 mL) was added TFA (20 mL). The mixturewas stirred for 1 h at r.t, concentrated, diluted with saturated aqueousNaHCO₃ (200 mL), and extracted with DCM three times. The combinedorganic layers were dried over MgSO₄, filtered, concentrated, andpurified by silica gel chromatography (40 g column, 0-50% MeOH in DCMwith 1% TEA) to provide 2.8 g (41% over 3 steps) of9-isopropyl-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dioneas a solid. LRMS (ES) m/z 370.2 (M+H). ¹H-NMR (Dichloromethane-d₂, 400MHz, ppm) δ 7.65-7.60 (m, 2H), 7.39-7.33 (m, 2H), 4.93-4.65 (m, 3H),4.02 (s, 2H), 3.46-3.40 (m, 1H), 3.16 (ddd, J=11.3, 8.2, 5.3 Hz, 1H),3.00 (ddd, J=11.3, 8.1, 6.7 Hz, 1H), 2.92 (d, J=12.1 Hz, 1H), 2.45 (ddd,J=13.6, 8.3, 6.7 Hz, 1H), 1.98 (ddd, J=13.5, 8.0, 5.2 Hz, 1H), 1.23 (d,J=6.8 Hz, 6H).

6. Synthesis of Compound 108

To a solution of9-Isopropyl-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione(50 mg, 0.14 mmol, 1.0 equiv) in DCM (2 mL) were added TEA (27 mg, 0.27mmol, 2.0 equiv) and methyl isocyanate (15 mg, 0.27 mmol, 2.0 equiv).The mixture was stirred for 30 min at r.t., concentrated, and purifiedby reverse phase HPLC (Phenomenex, gemini 5 micron C18 150×21.2 mm,10-100% acetonitrile in water both with 0.1% formic acid gradient over40 min) to provide 49 mg (85%) of9-isopropyl-N-methyl-7,10-dioxo-6-(4-(trifluoromethyenzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxamideas a white foamy solid. LRMS (ES) m/z 327.2 (M+H). ¹H-NMR (Methanol-d₄,400 MHz, ppm) δ 7.67-7.62 (m, 2H), 7.43-7.36 (m, 2H), 4.95 (d, J=17.0Hz, 1H), 4.79-4.65 (m, 2H), 4.18 (d, J=2.1 Hz, 2H), 3.95 (d, J=11.7 Hz,1H), 3.59 (d, J=11.7 Hz, 1H), 3.52-3.43 (m, 2H), 2.69 (s, 3H), 2.49-2.33(m, 2H), 1.24 (dd, J=6.8, 1.3 Hz, 6H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 108:

Compound No. LRMS (ES) m/z 107 M + H = 413.2 109 M + H = 489.2 1 M + H =467.2 110 M + H = 428.2 111 M + H = 490.2 112 M + H = 469.2 113 M + H =490.2 114 M + H = 493.2 115 M + H = 507.2 116 M + H = 441.2 117 M + H =455.2 118 M + H = 453.2 119 M + H = 407 120 M + H = 379 121 M + H = 393122 M + H = 419 123 M + H = 455

Example 6: Synthesis of Compound 76 1. Synthesis of Intermediate 6-2

To a solution of 3-amino-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylicacid (7.0 g, 30.4 mmol, 1.0 equiv) in MeOH (80 mL) was added4-(trifluoromethyl)benzaldehyde (5.6 g, 31.9 mmol, 1.05 equiv) and themixture was stirred for 1 h at r.t. To this mixture were added NaCNBH₃(2.9 g, 45.6 mmol, 1.5 equiv) and AcOH (0.5 mL). The mixture was stirredfor 2 h at r.t. to give a solution containing1-(tert-butoxycarbonyl)-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylicacid, which was used for next reaction without working up. LRMS (ES) m/z389.2 (M+H).

2. Synthesis of Intermediate 6-3

To the solution containing1-(tert-butoxycarbonyl)-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylicacid (30.4 mmol, 1.0 equiv) from the previous step were added DCM (100mL) and (trimethylsilyl)diazomethane (2 M in hexanes, 45.6 mL, 91.1mmol, 3.0 equiv). The mixture was stirred for 3 h at r.t., quenched withAcOH (5 g), concentrated onto 30 g SiO₂, and purified by silica gelchromatography (120 g, 0-100% EtOAc in hexanes) to provide 7.4 g (61%over 2 steps) of 1-(tert-butyl) 3-methyl3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-1,3-dicarboxylate as awhite solid. LRMS (ES) m/z 403.15 (M+H).

3. Synthesis of Intermediate 6-4

To a solution of 1-(tert-butyl) 3-methyl3-((4-(trifluoromethyl)benzyl)amino) pyrrolidine-1,3-dicarboxylate (7.4g, 18.4 mmol, 1.0 equiv) in DCM (50 mL) at 0° C. were added TEA (7.7 mL,84.9 mmol, 3.0 equiv) and chloroacetyl chloride (2.9 mL, 36.8 mmol, 2.0equiv). The ice bath was removed and the mixture was stirred for 3 h atr.t. The reaction was poured into saturated aqueous NH₄Cl (200 mL)solution and the layers were separated.

The aqueous layer was extracted with DCM (100 mL) three times. Thecombined organic layers were dried over MgSO₄ and concentrated to givean intermediate product, 1-(tert-butyl) 3-methyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine-1,3-dicarboxylate.LRMS (ES) m/z 379.1 (M+H-Boc).

4. Synthesis of Intermediate 6-5

To a solution of 1-(tert-butyl) 3-methyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine-1,3-dicarboxylate(18.4 mmol, 1.0 equiv assuming 100% yield) in ACN (300 mL) were addedisopropylamine (4.7 mL, 55.1 mmol, 3.0 equiv) and TEA (7.7 mL, 55.1mmol, 3.0 equiv). The mixture was heated at 80° C. for 15 h,concentrated, and purified by silica gel chromatography (80 g, 0-100%EtOAc in hexanes) to provide an intermediate product, tert-butyl9-isopropyl-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylateas a colored solid. LRMS (ES) m/z 414.15 (M+H-^(t)Bu).

5. Synthesis of Intermediate 6-6

To a solution of tert-butyl9-isopropyl-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate(18.4 mmol, 1.0 equiv) from the previous step in DCM (40 mL) was addedTFA (20 mL). The mixture was stirred for 1 h at r.t., concentrated,diluted with saturated NaHCO₃ (200 mL), and extracted with DCM threetimes. The combined organic layers were dried over MgSO₄, filtered,concentrated, and purified by silica gel chromatography (40 g column,0-50% MeOH in DCM with 1% TEA) to provide 2.8 g (41% over 3 steps) of9-isopropyl-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dioneas a dark tacky solid. LRMS (ES) m/z 370.2 (M+H). (Dichloromethane-d₂,400 MHz, ppm) δ 7.65-7.60 (m, 2H), 7.39-7.33 (m, 2H), 4.93-4.65 (m, 3H),4.02 (s, 2H), 3.46-3.40 (m, 1H), 3.16 (ddd, J=11.3, 8.2, 5.3 Hz, 1H),3.00 (ddd, J=11.3, 8.1, 6.7 Hz, 1H), 2.92 (d, J=12.1 Hz, 1H), 2.45 (ddd,J=13.6, 8.3, 6.7 Hz, 1H), 1.98 (ddd, J=13.5, 8.0, 5.2 Hz, 1H), 1.23 (d,J=6.8 Hz, 6H).

6. Synthesis of Compound 76

To a mixture of9-isopropyl-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione(50 mg, 0.14 mmol, 1.0 equiv), potassium tert-butoxide (61 mg, 0.54mmol, 4.0 equiv), Pd₂(dba)₃ (12 mg, 0.014 mmol, 0.1 equiv), and xantphos(16 mg, 0.027 mmol, 0.2 equiv) combined in a 5 mL microwave vial (5 mL)were added 4-bromopyridin-2(1H)-one (47 mg, 0.27 mmol, 2.0 equiv) anddioxane (2 mL). The mixture was sealed and heated at 150° C. in themicrowave reactor for 30 min, filtered, and purified by reverse phaseHPLC (Phenomenex, gemini 5 μm C18 150×21.2 mm, 10-100% acetonitrile inwater both with 0.1% formic acid gradient over 40 min) to afford 4.8 mg(8%) of9-isopropyl-2-(2-oxo-1,2-dihydropyridin-4-yl)-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dioneas a foamy solid. LRMS (ES) m/z 463.2 (M+H). (Methanol-d₄, 400 MHz, ppm)δ 8.18 (s, 1H), 7.62 (d, J=8.1 Hz, 2H), 7.41-7.36 (m, 2H), 7.20 (d,J=7.4 Hz, 1H), 5.88 (dd, J=7.4, 2.4 Hz, 1H), 5.30 (d, J=2.4 Hz, 1H),4.99 (d, J=16.9 Hz, 1H), 4.79-4.68 (m, 2H), 4.23 (d, J=2.0 Hz, 2H), 3.88(d, J=11.8 Hz, 1H), 3.66 (d, J=11.7 Hz, 1H), 3.57-3.49 (m, 2H),2.67-2.46 (m, 2H), 1.26 (d, J=6.8 Hz, 6H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 76:

Compound No. LRMS (ES) m/z 127 M + H = 412 128 M + H = 413 129 M + H =427 71 M + H = 414 72 M + H = 461.2 73 M + H = 448.2 74 M + H = 414 75M + H = 427 92 M + H = 431 77 M + H = 475.2 78 M + H = 416 79 M + H =414 80 M + H = 443 81 M + H = 429 82 M + H = 399.1 83 M + H = 439.2 84M + H = 427.2 85 M + H = 425.2 86 M + H = 443.2 93 M + H = 441.2 94 M +H = 441.1 87 M + H = 443.2 95 M + H = 438.2 96 M + H = 438.2 97 M + H =456.1 98 M + H = 456.2 88 M + H = 472.2 89 M + H = 490.2 90 M + H =472.1 91 M + H = 490.1

Example 7: Synthesis of Compound 49 1. Synthesis of Intermediate 7-2

To a solution of 1-(tert-butyl)3-methyl-3-aminoazetidine-1,3-dicarboxylate (5.0 g, 21.7 mmol, 1.0equiv) in MeOH (50 mL) was added 4-chlorobenzaldehyde (4.5 g, 32.6 mmol,1.5 equiv). The mixture was stirred for 1 h at r.t. To the mixture wereadded NaCNBH₃ (1.4 g, 21.7 mmol, 1.0 equiv) and AcOH (1 mL). The mixturewas continued to stir for 4 h, concentrated under reduced pressure, andpartitioned between DCM (60 mL) and saturated sodium bicarbonate (60mL). The layers were separated, and the aqueous phase was extracted withDCM (25 mL). The combined organic layers were dried over sodium sulfate,filtered through celite, concentrated under reduced pressure, andpurified by silica gel chromatography (80 g column, 0-100% EtOAc inhexanes) to provide 6.0 g (78%) of 1-(tert-butyl) 3-methyl3-((4-chlorobenzyl)amino) azetidine-1,3-dicarboxylate. LRMS (ES) m/z355.2 (M+H). ¹H-NMR (Methylenechloride-d₂, 400 MHz, ppm) δ 7.35 (s, 4H),4.19 (d, J=8.8 Hz, 2H), 3.86 (d, J=8.8 Hz, 2H), 3.82 (s, 3H), 3.68 (s,2H), 1.46 (s, 9H).

2. Synthesis of Intermediate 7-3

To a solution of 1-(tert-butyl) 3-methyl3-((4-chlorobenzyl)amino)azetidine-1,3-dicarboxylate (6.0 g, 16.9 mmol,1.0 equiv) in DCM (50 mL) cooled to 0° C. were added TEA (7.1 mL, 50.7mmol, 3.0 equiv) and chloroacetyl chloride (2.7 mL, 33.8 mmol, 2.0equiv). The mixture was stirred for 3 h at r.t and poured into saturatedaqueous NH₄Cl (200 mL) solution. The aqueous layer was extracted withDCM (100 mL) three times. The combined organic layers were dried overMgSO₄ and concentrated to give an intermediate product, 1-(tert-butyl)3-methyl3-(2-chloro-N-(4-chlorobenzyl)acetamido)azetidine-1,3-dicarboxylate.LRMS (ES) m/z 431.1 (M+H).

3. Synthesis of Intermediate 7-4

To a solution of 1-(tert-butyl) 3-methyl3-(2-chloro-N-(4-chlorobenzyl)acetamido)azetidine-1,3-dicarboxylate(16.9 mmol, 1.0 equiv) in ACN (300 mL) were added isopropylamine (2.9mL, 33.9 mmol, 2.0 equiv) and TEA (7.1 mL, 50.8 mmol, 3.0 equiv). Themixture was heated at 80° C. for 15 h, cooled to r.t., concentrated, andpurified by silica gel chromatography (80 g, 0-100% EtOAc in hexanes) toprovide 6.5 g (91%) of tert-butyl5-(4-chlorobenzyl)-8-isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylateas a colored solid. LRMS (ES) m/z 366.1 (M+H-^(t)Bu).

4. Synthesis of Intermediate 7-5

To a solution of tert-butyl5-(4-chlorobenzyl)-8-isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(6.5 g, 15.4 mmol, 1.0 equiv) in DCM (40 mL) was added TFA (12 mL). Themixture was stirred for 1 h at r.t., concentrated, diluted withsaturated NaHCO₃ (200 mL), and extracted with DCM three times. Thecombined organic washes were dried over MgSO₄, filtered, concentrated,and purified by silica gel chromatography (40 g column, 0-50% MeOH inDCM) to provide 4.1 g (83%) of5-(4-chlorobenzyl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione asan off-white solid. LRMS (ES) m/z 322.1 (M+H). ¹H-NMR(Dichloromethane-d₂, 400 MHz, ppm) δ 7.36-7.32 (m, 2H), 7.28-7.24 (m,2H), 5.16 (s, 2H), 4.85 (p, J=6.9 Hz, 1H), 4.30-4.19 (m, 4H), 4.00 (s,2H), 1.24 (d, J=6.8 Hz, 6H).

5. Synthesis of Compound 49

To a mixture of5-(4-chlorobenzyl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione(50 mg, 0.16 mmol, 1.0 equiv), potassium tert-butoxide (70 mg, 0.62mmol, 4.0 equiv), Pd₂(dba)₃ (7 mg, 0.008 mmol, 0.05 equiv), and xantphos(9 mg, 0.016 mmol, 0.1 equiv) combined in a microwave vial (5 mL) wereadded 4-bromo-2,6-dimethylpyridine (58 mg, 0.31 mmol, 2.0 equiv) anddioxane (2 mL). The mixture was sealed, heated at 150° C. in themicrowave reactor for 10 min, filtered, and purified by reverse phaseHPLC (Phenomenex, gemini 5 μm C18 150×21.2 mm, 10-100% acetonitrile inwater both with 0.1% formic acid gradient over 40 min) to afford 7.1 mg(10%) of5-(4-chlorobenzyl)-2-(2,6-dimethylpyridin-4-yl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dioneas a white foamy solid. LRMS (ES) m/z 427.15 (M+H).(Methylenechloride-d₂, 400 MHz, ppm) δ 7.42-7.33 (m, 2H), 7.24-7.17 (m,2H), 6.07 (s, 2H), 4.95 (s, 2H), 4.84 (p, J=6.9 Hz, 1H), 4.62 (dd,J=9.5, 1.1 Hz, 2H), 4.25 (dd, J=9.5, 1.1 Hz, 2H), 4.06 (s, 2H), 2.57 (s,6H), 1.25 (d, J=6.8 Hz, 6H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 49:

Compound No. LRMS (ES) m/z 2 M + H = 398 3 M + H = 416 4 M + H = 432 5M + H = 432 6 M + H = 399.1 7 M + H = 399 8 M + H = 399 9 M + H = 413 10M + H = 413 11 M + H = 400 12 M + H = 400 13 M + H = 413.1 14 M + H =413.1 15 M + H = 413.1 16 M + H = 413 17 M + H = 417 18 M + H = 417 19M + H = 400 21 M + H = 402.2 22 M + H = 405.1 23 M + H = 400 24 M + H =400 25 M + H = 400 26 M + H = 402.2 27 M + H = 424.1 28 M + H = 415.1 29M + H = 449.1 30 M + H = 393.2 31 M + H = 447.2 32 M + H = 405.1 33 M +H = 405.1 34 M + H = 439.1 35 M + H = 457.2 36 M + H = 443.1 37 M + H =442.1 38 M + H = 456.2 39 M + H = 473.1 40 M + H = 448.1 41 M + H =388.1 42 M + H = 429.3 43 M + H = 419.1 44 M + H = 419.1 45 M + H =404.1 46 M + H = 433.2 47 M + H = 461.1 48 M + H = 449.1 50 M + H =434.1 51 M + H = 430.2 52 M + H = 416.1 53 M + H = 468.1 54 M + H =443.1 55 M + H = 414.2 56 M + H = 434.1 57 M + H = 444.1 58 M + H =484.2 59 M + H = 472.2 60 M + H = 434.1 61 M + H = 434.1 62 M + H =498.2 63 M + H = 424.2

Example 8: Synthesis of Compound 142 1. Synthesis of Intermediate 8-2

A mixture of azetin-3-ol hydrochloride (1.3 g, 11.9 mmol, 1.0 equiv),L(−)-proline (0.55 g, 4.8 mmol, 0.4 equiv), copper (I) iodide (0.45 g,2.4 mmol, 0.2 equiv) and cesium carbonate (9.7 g, 29.7 mmol, 2.5 equiv)combined in a flask with a septum was vacuum-nitrogen purged 3 times. Tothis container were added iodobenzene (2.0 mL, 18 mmol, 1.5 equiv) anddry DMSO (30 mL). The mixture was heated at 90° C. for 15 h, dilutedwith water, and extracted with EA three times. The combined organiclayers were dried over magnesium sulfate, filtered, evaporated, andpurified by silica gel chromatography (40 g, 60 5 μm, 0-100% ethylacetate in hexanes gradient over 14 min) to give 1.6 g (90%) of1-phenylazetidin-3-ol as a clear colorless oil. LRMS (ES) m/z 150 (M+H).¹H NMR (400 MHz, Methylene Chloride-d₂) δ 7.27-7.20 (m, 2H), 6.81-6.74(m, 1H), 6.55-6.49 (m, 2H), 4.80-4.72 (m, 1H), 4.23-4.16 (m, 2H),3.71-3.65 (m, 2H).

2. Synthesis of Intermediate 8-3

To a solution of oxalyl chloride (1.5 mL, 17 mmol, 1.7 equiv) in dry DCM(15 mL) was added DMSO (2.4 mL, 34 mmol, 3.3 equiv) dropwise at −78° C.The mixture was stirred for 10 min at −78° C., followed by addition of1-phenylazetidin-3-ol (1.5 g, 10.3 mmol, 1.0 equiv) in dry DCM (15 mL)dropwise and stirred for 1 h. To this mixture at −78° C. was added TEA(10.0 mL, 71.9 mmol, 7.0 equiv). The mixture was continued to stir for 1h at −78° C., diluted with saturated sodium bicarbonate, and extractedwith DCM three times. The combined organic extractions were washed withbrine, dried over magnesium sulfate, filtered, evaporated, and purifiedby silica gel chromatography (40 g, 60 um, 0-10% ethyl acetate inhexanes, gradient over 28 min) to give 0.96 g (63%) of1-phenylazetidin-3-one as a clear yellow oil. LRMS (ES) m/z 148 (M+H).¹H NMR (400 MHz, Methylene Chloride-d₂) δ 7.36-7.29 (m, 2H), 6.92-6.87(m, 1H), 6.69-6.63 (m, 2H), 4.70 (s, 4H).

3. Synthesis of Intermediate 8-4

1-Phenylazetidin-3-one (0.31 g, 2.1 mmol, 1.0 equiv) and(1S)-1-[4-(trifluoromethyl)phenyl]ethan-1-amine (0.44 g, 2.3 mmol, 1.1equiv) were combined in dry MeOH (3 mL) and the mixture was heated at60° C. for 1 h. To this mixture cooled to 0° C. were added acetic acid(0.13 mL, 2.3 mmol, 1.1 equiv) and sodium cyanide (0.11 g, 2.3 mmol, 1.1equiv) sequentially. The mixture was heated at 60° C. for 15 h, dilutedwith water, and extracted with EA three times. The combined organicwashes were dried over magnesium sulfate, filtered, evaporated, andpurified by silica gel chromatography (12 g, 60 um, 0-20% ethyl acetatein hexanes, gradient over 22 min) to give 0.46 g (62%) of(S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carbonitrileas a clear colorless oil. LRMS (ES) m/z 346 (M+H). ¹H NMR (400 MHz,Methylene Chloride-d₂) δ 7.69-7.65 (m, 2H), 7.64-7.59 (m, 2H), 7.26-7.19(m, 2H), 6.85-6.79 (m, 1H), 6.42-6.38 (m, 2H), 4.38-4.35 (m, 1H), 4.26(q, J=6.6 Hz, 1H), 3.92-3.88 (m, 1H), 3.83-3.79 (m, 1H), 3.38-3.34 (m,1H), 1.48 (d, J=6.6 Hz, 3H).

4. Synthesis of Intermediate 8-5

To a solution of(S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carbonitrile (0.20 g, 0.58 mmol, 1.0 equiv) in dry MeOH (2mL) was added aqueous sodium hydroxide (1N, 1.2 mL, 1.2 mmol, 2.0equiv). The mixture was heated at 100° C. for 15 h, cooled to r.t.,neutralized with HCl (1M, 1.2 mL, 1.2 mmol, 2.0 equiv), and extractedwith EA twice. The combined organic washes were dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to give 89 mg(42%) of (S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carboxylic acid as a pale yellow solid.

5. Synthesis of Intermediate 8-6

To a solution of(S)-1-Phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carboxylic acid (89 mg, 0.24 mmol, 1.0 equiv) in a mixtureof DCM (1 mL) and methanol (1 mL) was added (trimethylsilyl)diazomethanein hexanes (2 M, 0.37 mL, 0.74 mmol, 3.0 equiv) dropwise. The mixturewas stirred at r.t. for 2 h, concentrated, and purified by silica gelchromatography (12 g, 60 micron, 0-30% ethyl acetate in hexanes,gradient over 22 min) to give 79 mg (86%) of methyl(S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carboxylate as a clear colorless oil. LRMS (ES) m/z379 (M+H).

6. Synthesis of Intermediate 8-7

To a solution of methyl(S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carboxylate (79 mg, 0.21 mmol, 1.0 equiv) in DCM (1mL) were added TEA (0.18 mL, 1.2 mmol, 6.0 equiv) and chloroacetylchloride (0.067 mL, 0.84 mmol, 4.0 equiv) dropwise. The mixture wasstirred for 30 min at r.t., diluted with saturated sodium bicarbonate,and extracted with DCM. The organic layer was dried over magnesiumsulfate, filtered, and concentrated to give 140 mg of methyl(S)-3-(2-chloro-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamido)-1-phenylazetidine-3-carboxylateas a red oil. LRMS (ES) m/z 455 (M+H).

7. Synthesis of Compound 142

To a solution of methyl(S)-3-(2-chloro-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamido)-1-phenylazetidine-3-carboxylate (0.21 mmol, 1.0 equiv) in dryACN (7.5 mL) were added triethylamine (0.13 mL, 0.94 mmol, 4.5 equiv)and isopropylamine (0.053 mL, 0.62 mmol, 3.0 equiv). The mixture washeated at 80° C. for 15 h, concentrated, and purified by reverse phaseHPLC (Phenomenex, gemini 5u C18 150×21.2 mm, 10-100% acetonitrile inwater both with 0.1% formic acid gradient over 25 min) to give 19 mg(20% over 2 steps) of(S)-8-isopropyl-2-phenyl-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione.LRMS (ES) m/z 446 (M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 7.67-7.62 (m,2H), 7.60-7.55 (m, 2H), 7.22-7.16 (m, 2H), 6.79-6.73 (m, 1H), 6.49-6.44(m, 2H), 5.74-5.65 (m, 1H), 4.73 (hept, J=6.8 Hz, 1H), 4.46-4.41 (m,1H), 4.37-4.32 (m, 1H), 4.27-4.21 (m, 1H), 4.13-4.09 (m, 1H), 4.07-3.96(m, 2H), 2.01 (d, J=7.0 Hz, 3H), 1.23 (d, J=6.8 Hz, 6H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 142:

Compound No. LRMS (ES) m/z 138 M + H = 447.2 139 M + H = 427.2 140 M + H= 446.2 141 M + H = 446.2

Example 9: Synthesis of Compound 327 1. Synthesis of Intermediate 9-2

To solution of 1-phenyl-2-oxo-3-pyrrolidine carboxylic acid (0.95 g, 4.6mmol, 1.0 equiv) in a mixture of DCM (10 mL) and MeOH (10 mL) cooled to0° C. was added (trimethylsilyl)diazomethane in hexanes (2 M, 7.0 mL, 14mmol, 3.0 equiv) dropwise. The mixture was stirred for 30 min at r.t.,concentrated, and purified by silica gel chromatography (24 g, 0-10%ethyl acetate in hexanes, gradient over 11.5 min) to give 1.02 g (100%)of methyl 2-oxo-1-phenylpyrrolidine-3-carboxylate as a white solid. LRMS(ES) m/z 220 (M+H). ¹H NMR (400 MHz, Methylene Chloride-d₂) δ 7.66-7.61(m, 2H), 7.45-7.38 (m, 2H), 7.25-7.19 (m, 1H), 4.02-3.95 (m, 1H),3.91-3.84 (m, 1H), 3.81 (s, 3H), 3.68-3.63 (m, 1H), 2.59-2.50 (m, 1H),2.48-2.38 (m, 1H).

2. Synthesis of Intermediate 9-3

To a mixture of methyl 2-oxo-1-phenylpyrrolidine-3-carboxylate (0.30 g,1.4 mmol, 1.0 equiv) and ytterbium (III) trifluoromethane sulfonate(0.255 g, 0.41 mmol, 0.30 equiv) in EA (9 mL) was added NBS (0.244 g,1.4 mmol, 1.0 equiv). The mixture was stirred for 30 min at r.t.,concentrated, and purified by silica gel chromatography (24 g, 0-30%Ethyl acetate in hexanes, gradient over 11.5 min) to give 408 mg (100%)of 3-bromo-2-oxo-1-phenylpyrrolidine-3-carboxylate as a white solid.LRMS (ES) m/z 298 (M+H). ¹H NMR (400 MHz, Methylene Chloride-d₂) δ7.68-7.62 (m, 2H), 7.48-7.42 (m, 2H), 7.30-7.24 (m, 1H), 4.04-3.97 (m,1H), 3.94-3.88 (m, 4H), 3.19-3.10 (m, 1H), 2.72-2.64 (m, 1H).

3. Synthesis of Intermediate 9-4

To a solution of 3-bromo-2-oxo-1-phenylpyrrolidine-3-carboxylate (0.113g, 0.38 mmol, 1.0 equiv) in DMF (1 mL) were added TEA (0.21 mL, 1.5mmol, 4.0 equiv) and 4-(trifluoromethyl)benzyl amine (0.11 mL, 0.76mmol, 2.0 equiv). The mixture was stirred for 15 min at r.t., heated at50° C. for 1 h, diluted with water, and extracted with EA three times.The combined organic extractions were washed once with brine, dried overmagnesium sulfate, filtered, concentrated, purified by silica gelchromatography (12 g, 60 um, 0-40% ethyl acetate in hexanes, gradientover 22 min), and purified again by silica gel chromatography (12 g, 60um, 0-30% ethyl acetate in hexanes, gradient over 22 min) to give 24 mg(16%) of methyl2-oxo-1-phenyl-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylateas a clear colorless oil. LRMS (ES) m/z 393 (M+H). ¹H NMR (400 MHz,Methylene Chloride-d₂) δ 7.59-7.54 (m, 2H), 7.54-7.49 (m, 2H), 7.49-7.44(m, 2H), 7.35-7.29 (m, 2H), 7.15-7.09 (m, 1H), 3.95-3.84 (m, 2H),3.81-3.69 (m, 5H), 2.68-2.61 (m, 1H), 2.24-2.14 (m, 1H).

4. Synthesis of Intermediate 9-5

To a solution of methyl2-oxo-1-phenyl-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylate (0.024 g, 0.061 mmol, 1.0 equiv) in DCM (1 mL)were added TEA (0.051 mL, 0.36 mmol, 6.0 equiv) and chloroacetylchloride (0.022 mL, 0.24 mmol, 4.0 equiv). The mixture was stirred for15 minutes. To this mixture were added additional TEA (0.051 mL, 0.36mmol, 6.0 equiv) and chloroacetyl chloride (0.022 mL, 0.24 mmol, 4.0equiv) twice. The mixture was stirred for 15 minutes, diluted withdichloroethane (2 mL), heated at 83° C. overnight, cooled to r.t.,diluted with saturated sodium bicarbonate, and extracted with DCM threetimes. The combined organic extractions were then washed once withbrine, dried over magnesium sulfate, filtered, and concentrated to give29 mg (quantitative) of methyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-2-oxo-1-phenylpyrrolidine-3-carboxylateas a brown solid. LRMS (ES) m/z 469 (M+H).

5. Synthesis of Compound 327

To a solution of methyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-2-oxo-1-phenylpyrrolidine-3-carboxylate(29 mg, 0.079 mmol, 1.0 equiv) in ACN (4 mL) were added TEA (0.067 mL,0.48 mmol, 7.8 equiv) and isopropylamine (0.027 mL, 0.32 mmol, 6.3equiv). The mixture was heated at 80° C. for 1 h, concentrated, andpurified by reverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm,10-100% acetonitrile in water both with 0.1% formic acid gradient over25 min) to give 15 mg (20%) of9-isopropyl-2-phenyl-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-1,7,10-trioneas a clear colorless oil. LRMS (ES) m/z 460 (M+H). ¹H NMR (400 MHz,Methanol-d₄) δ 7.64-7.59 (m, 2H), 7.57-7.53 (m, 2H), 7.53-7.49 (m, 2H),7.42-7.36 (m, 2H), 7.27-7.21 (m, 1H), 4.99-4.92 (m, 1H), 4.76-4.67 (m,2H), 4.33-4.16 (m, 2H), 4.16-4.08 (m, 1H), 3.87-3.78 (m, 1H), 2.86-2.77(m, 1H), 2.59-2.48 (m, 1H), 1.28-1.20 (m, 6H).

Example 10: Synthesis of Compound 328 1. Synthesis of Intermediate 10-2

Azetin-3-ol hydrochloride (1.3 g, 11.9 mmol, 1.0 equiv), L(−)-proline(0.55 g, 4.8 mmol, 0.4 equiv), copper (I) iodide (0.45 g, 2.4 mmol, 0.2equiv) and cesium carbonate (9.7 g, 29.7 mmol, 2.5 equiv) were combinedin a flask with a septum which was then vacuum-nitrogen purged 3 times.To this container were added iodobenzene (2.0 mL, 18 mmol, 1.5 equiv)and dry dimethylsulfoxide (30 mL). The mixture was heated at 90° C. for15 h, diluted with water, and extracted with EA three times. Thecombined organic layers were dried over magnesium sulfate, filtered,evaporated, and purified by silica gel chromatography (40 g, 60 um,0-100% ethyl acetate in hexanes gradient over 14 min) to give 1.6 g(90%) of 1-phenylazetidin-3-ol as a clear colorless oil. LRMS (ES) m/z150 (M+H). ¹H NMR (400 MHz, Methylene Chloride-d₂) δ 7.27-7.20 (m, 2H),6.81-6.74 (m, 1H), 6.55-6.49 (m, 2H), 4.80-4.72 (m, 1H), 4.23-4.16 (m,2H), 3.71-3.65 (m, 2H).

2. Synthesis of Intermediate 10-3

To a solution of oxalyl chloride (1.5 mL, 17 mmol, 1.7 equiv) in dry DCM(15 mL) was added DMSO (2.4 mL, 34 mmol, 3.3 equiv) dropwise at −78° C.The mixture was stirred for 10 min at −78° C. and added1-phenylazetidin-3-ol (1.5 g, 10.3 mmol, 1.0 equiv) in dry DCM (15 mL)dropwise, stirred for 1 h, added TEA (10.0 mL, 71.9 mmol, 7.0 equiv),continued to stir for 1 h at −78° C., diluted with saturated sodiumbicarbonate, and extracted with DCM three times. The combined organicextractions were washed with brine, dried over magnesium sulfate,filtered, evaporated, and purified by silica gel chromatography (40 g,60 um, 0-10% ethyl acetate in hexanes, gradient over 28 min) to give0.96 g (63%) of 1-phenylazetidin-3-one as a clear yellow oil. LRMS (ES)m/z 148 (M+H). ¹H NMR (400 MHz, Methylene Chloride-d₂) δ 7.36-7.29 (m,2H), 6.92-6.87 (m, 1H), 6.69-6.63 (m, 2H), 4.70 (s, 4H).

3. Synthesis of Intermediate 10-4

1-Phenylazetidin-3-one (0.31 g, 2.1 mmol, 1.0 equiv) and(1S)-1-[4-(trifluoromethyl)phenyl]ethan-1-amine (0.44 g, 2.3 mmol, 1.1equiv) were combined in dry MeOH (3 mL) and the mixture was heated at60° C. for 1 h. To this mixture cooled to 0° C. were added acetic acid(0.13 mL, 2.3 mmol, 1.1 equiv) and sodium cyanide (0.11 g, 2.3 mmol, 1.1equiv) sequentially. The mixture was heated at 60° C. for 15 h, dilutedwith water, and extracted with EA three times. The combined organicwashes were dried over magnesium sulfate, filtered, evaporated, andpurified by silica gel chromatography (12 g, 60 um, 0-20% ethyl acetatein hexanes, gradient over 22 min) to give 0.46 g (62%) of(S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carbonitrileas a clear colorless oil. LRMS (ES) m/z 346 (M+H). ¹H NMR (400 MHz,Methylene Chloride-d₂) δ 7.69-7.65 (m, 2H), 7.64-7.59 (m, 2H), 7.26-7.19(m, 2H), 6.85-6.79 (m, 1H), 6.42-6.38 (m, 2H), 4.38-4.35 (m, 1H), 4.26(q, J=6.6 Hz, 1H), 3.92-3.88 (m, 1H), 3.83-3.79 (m, 1H), 3.38-3.34 (m,1H), 1.48 (d, J=6.6 Hz, 3H).

4. Synthesis of Intermediate 10-5

To a solution of(S)-1-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carbonitrile (0.272 g, 0.787 mmol, 1.0 equiv) in DCM (3 mL)were added TEA (0.33 mL, 2.4 mmol, 3.0 equiv) and chloroacetyl chloride(0.12 mL, 1.6 mmol, 2.0 equiv) dropwise. The mixture was stirred for 15min. To this mixture were added TEA (0.33 mL, 2.4 mmol, 3.0 equiv) andchloroacetyl chloride (0.12 mL, 1.6 mmol, 2.0 equiv). The mixture wasstirred for 30 min, diluted with saturated sodium bicarbonate, andextracted with DCM twice. The combined extractions were dried overmagnesium sulfate, filtered, and concentrated to give 332 mg (100%) of(S)-2-chloro-N-(3-cyano-1-phenylazetidin-3-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamideas a red oil. LRMS (ES) m/z 422 (M+H). ¹H NMR (400 MHz, MethyleneChloride-d₂) δ 7.72-7.67 (m, 2H), 7.59-7.54 (m, 2H), 7.28-7.21 (m, 2H),6.89-6.84 (m, 1H), 6.45-6.41 (m, 2H), 5.19-5.11 (m, 1H), 4.49-4.45 (m,1H), 4.42-4.39 (m, 1H), 4.07-3.94 (m, 3H), 3.83-3.79 (m, 1H), 1.96 (d,J=7.1 Hz, 3H).

5. Synthesis of Intermediate 10-6

To a solution of(S)-2-chloro-N-(3-cyano-1-phenylazetidin-3-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide(0.332 g, 0.787 mmol, 1.0 equiv) in dry DCM (3 mL) was addedisopropylamine (3.4 mL, 39 mmol, 50 equiv). The mixture was stirred for3 days at r.t., concentrated, and purified by silica gel chromatography(12 g, 60 um, 0-10% methanol in dichloromethane, gradient over 22 min)to give 314 mg (90%) of(S)—N-(3-cyano-1-phenylazetidin-3-yl)-2-(isopropylamino)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide as a clear slightly yellow oil. LRMS (ES) m/z 445 (M+H). ¹HNMR (400 MHz, Methylene Chloride-d₂) δ 7.64-7.60 (m, 2H), 7.43-7.38 (m,2H), 7.24-7.18 (m, 2H), 6.82-6.77 (m, 1H), 6.43-6.39 (m, 2H), 5.90-5.80(m, 1H), 4.60-4.46 (m, 1H), 4.41-4.35 (m, 1H), 4.30-4.21 (m, 1H),4.07-3.99 (m, 2H), 3.90-3.83 (m, 1H), 3.79-3.73 (m, 1H), 1.87 (d, J=7.2Hz, 3H), 1.28-1.21 (m, 6H).

6. Synthesis of Compound 328

To a solution of(S)—N-(3-Cyano-1-phenylazetidin-3-yl)-2-(isopropylamino)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide(54 mg, 0.12 mmol, 1.0 equiv) in dry toluene (0.5 mL) was heated to 150°C. in the microwave reactor for 30 min. The mixture was concentrated andpurified by reverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm,10-100% acetonitrile in water both with 0.1% formic acid gradient over25 min) to give 28 mg (52%) of(S)-9-imino-8-isopropyl-2-phenyl-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonan-6-oneas a clear colorless oil. LRMS (ES) m/z 445 (M+H). ¹H NMR (400 MHz,Methanol-d₄) δ 8.38 (s, 1H), 7.69-7.63 (m, 2H), 7.56-7.50 (m, 2H),7.25-7.19 (m, 2H), 6.89-6.82 (m, 1H), 6.56-6.48 (m, 2H), 5.73-5.61 (m,1H), 4.54-4.45 (m, 2H), 4.32-4.14 (m, 5H), 1.86 (d, J=7.1 Hz, 3H),1.46-1.39 (m, 6H).

Example 11: Synthesis of Compound 332 1. Synthesis of Intermediate 11-2

To a solution of racemic3-amino-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.00 g,8.69 mmol) in NaOH (1 M, 15 mL) was added di-tert-butyl dicarbonate(3.79 g, 17.37 mmol, 2.0 equiv.) in 1,4-dioxane (15 mL). The resultingmixture was stirred at r.t. for 18 h. The pH was adjusted to 3 using 3 Maqueous HCl, and the resulting mixture was extracted twice with EA(total volume=125 mL). The organic extracts were combined, washed withbrine, dried over sodium sulfate, and concentrated under reducedpressure to provide1-(tert-butoxycarbonyl)-3-((tert-butoxycarbonyl)amino)pyrrolidine-3-carboxylicacid (2.93 g, 7.98 mmol, 92% yield) as a sticky foam which was used inthe following step without additional purification. LRMS (APCI) m/z329.1 (M−H). ¹H NMR (400 MHz, DMSO-d₆) δ 12.68 (s, 1H), 7.54 (s, 1H),3.74-3.66 (m, 1H), 3.51 (dd, J=20.3, 11.4 Hz, 1H), 3.34-3.26 (m, 2H),2.21-2.04 (m, 2H), 1.39 (s, 18H).

2. Synthesis of Intermediate 11-3

To a solution of1-(tert-butoxycarbonyl)-3-((tert-butoxycarbonyl)amino)pyrrolidine-3-carboxylicacid (2.93 g, 7.98 mmol) in a mixture of DCM (40 mL) and MeOH (20 mL)was added (diazomethyl)trimethylsilane (11.97 mL of 2.0 M in hexanes,23.95 mmol, 3.0 equiv.) portionwise. The resulting solution was stirredat r.t. for 30 minutes, quenched with glacial acetic acid (1 mL) untilgas evolution ceased, and concentrated under reduced pressure. Theremaining residue was dissolved in DCM (100 mL) and washed with 2 Maqueous K₂CO₃ (25 mL). The organic phase was dried over sodium sulfate,concentrated, and purified with silica gel using 30% EA/Hex to give the2.12 g (77%) of 1-(tert-butyl) 3-methyl3-((tert-butoxycarbonyl)amino)pyrrolidine-1,3-dicarboxylate as acolorless sticky solid. LRMS (APCI) m/z 245.2 (M+H) (Boc loss). ¹H NMR(400 MHz, Methanol-d₄) δ 3.84-3.75 (m, 1H), 3.64 (s, 3H), 3.57-3.44 (m,1H), 3.43-3.30 (m, 2H), 2.24-2.13 (m, 1H), 2.12-2.02 (m, 1H), 1.41-1.32(m, 18H).

3. Synthesis of Intermediates 11-4A and 11-4B

This step followed the published method in Chem. Pharm. Bull. 42(8)1302-1306, 1995. To a mixture of ruthenium oxide hydrate (386 mg, 2.90mmol, 0.5 equiv.) and sodium periodate (6.21 g, 29.04 mmol, 5.0 equiv.)in a round-bottom flask (250 mL) were added water (25 mL) and1-(tert-butyl) 3-methyl3-((tert-butoxycarbonyl)amino)pyrrolidine-1,3-dicarboxylate (2.00 g,5.81 mmol, 1.0 equiv.) in EA (25 mL). The resulting biphasic mixture wasstirred vigorously for 3 h, diluted with additional EA (50 mL), andfiltered through celite. The layers were separated and the aqueous phasewas extracted once with EA (50 mL). The organic phases were combined anddiluted with MeOH (5 mL). The resulting black solution was stirred atr.t. for 30 minutes and filtered again through celite. The solvent wasevaporated in vacuo and the remaining solid residue was purified withsilica gel using 30% EA/Hex to provide 1.44 g (69%) of 1-(tert-butyl)3-methyl3-((tert-butoxycarbonyl)amino)-5-oxopyrrolidine-1,3-dicarboxylate(11-4A) and 437 mg (21%) of 1-(tert-butyl) 3-methyl3-((tert-butoxycarbonyl)amino)-2-oxopyrrolidine-1,3-dicarboxylate(11-4B), both visualized on TLC with KMnO₄ stain.

Characterization for Intermediate 11-4A: LRMS (APCI) m/z 203.1 (M+H)(Boc loss and tert-butyl loss). ¹H NMR (400 MHz, Methanol-d₄) δ 4.21 (d,J=11.5 Hz, 1H), 3.95 (d, J=11.5 Hz, 1H), 3.78 (s, 3H), 3.13 (d, J=17.5Hz, 1H), 2.80 (dd, J=17.5, 0.8 Hz, 1H), 1.55 (s, 9H), 1.46 (s, 9H).

Characterization for Intermediate 11-4B: LRMS (APCI) m/z 203.1 (M+H)(Boc loss and tert-butyl loss). ¹H NMR (400 MHz, Methanol-d₄) δ3.94-3.74 (m, 5H), 2.63 (ddd, J=13.4, 7.9, 2.2 Hz, 1H), 2.42 (dt,J=13.5, 9.2 Hz, 1H), 1.56 (s, 9H), 1.46 (s, 9H).

4. Synthesis of Intermediate 11-5

To a solution of 1-(tert-butyl) 3-methyl3-((tert-butoxycarbonyl)amino)-5-oxopyrrolidine-1,3-dicarboxylate (916mg, 2.56 mmol) in DCM (5 mL) was added TFA (5 mL). The resulting mixturewas stirred at r.t. for 30 minutes. The solvents were removed underreduced pressure and dried under high vacuum to provide 692 mg(quantitative yield) of methyl 3-amino-5-oxopyrrolidine-3-carboxylate asTFA salt without further purification. LRMS (APCI) m/z 159.1 (M+H).

5. Synthesis of Intermediate 11-6

To a mixture of methyl 3-amino-5-oxopyrrolidine-3-carboxylate TFA salt(692 mg, 2.55 mmol) and p-chlorobenzaldehyde (1.07 g, 7.63 mmol, 3.0equiv.) in a mixture of THF (30 mL) and dichloroethane (10 mL) stirredfor 15 minutes was added NaBH(OAc)₃ (2.69 g, 12.71 mmol, 5.0 equiv.).The resulting mixture was stirred at r.t. for 1 h, during which time ahomogeneous solution was observed. The solvents were evaporated underreduced pressure and the remaining residue was partitioned between DCM(60 mL) and saturated aqueous NaHCO₃ (60 mL). The aqueous phase wasextracted with DCM (25 mL). The organic phases were combined, dried oversodium sulfate, filtered through celite, and concentrated under reducedpressure. The remaining residue was purified with silica gel using agradient from 0%-100% EA/Hex as eluent to provide 548 mg (76%) of methyl3-((4-chlorobenzyl)amino)-5-oxopyrrolidine-3-carboxylate. LRMS (APCI)m/z 159.1 (M+H).

6. Synthesis of Intermediate 11-7

To a mixture of CuI (25 mg, 0.13 mmol, 0.5 equiv.) and K₂CO₃ (143 mg,1.03 mmol, 4.0 equiv.) were added methyl3-((4-chlorobenzyl)amino)-5-oxopyrrolidine-3-carboxylate (73 mg, 0.26mmol, 1.0 equiv.) in anhydrous 1,4-dioxane (2 mL), 2-iodopyridine (41μL, 0.39 mmol, 1.5 equiv.) and N,N-dimethylethylenediamine (13 μL, 0.13mmol, 0.5 equiv.) sequentially. The resulting mixture was flushed withnitrogen, sealed and heated at 115° C. in an oil bath for 18 h. Thereaction was filtered through a syringe filter, concentrated underreduced pressure, and purified with reverse phase HPLC using 10%-100%ACN/water (both with 0.1% formic acid; Phenomenex Gemini C18 5 microncolumn) to provide 59 mg (62%) of methyl3-((4-chlorobenzyl)amino)-5-oxo-1-(pyridin-2-yl)pyrrolidine-3-carboxylate.LRMS (APCI) m/z 360.1 (M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 8.40-8.23(m, 2H), 7.79 (ddd, J=8.3, 7.3, 2.1 Hz, 1H), 7.33 (d, 2H), 7.26 (d, 2H),7.14 (ddd, J=7.3, 4.8, 1.1 Hz, 1H), 4.37 (d, J=11.8 Hz, 1H), 4.19 (dd,J=11.7, 0.7 Hz, 1H), 3.81 (s, 3H), 3.73 (d, J=2.1 Hz, 2H), 3.22 (d,J=17.1 Hz, 1H), 2.80 (dd, J=17.2, 0.7 Hz, 1H).

7. Synthesis of Compound 332

To a solution of methyl3-((4-chlorobenzyl)amino)-5-oxo-1-(pyridin-2-yl)pyrrolidine-3-carboxylate(59 mg, 0.16 mmol) in DCM (3 mL) was added Et₃N (229 μL, 1.64 mmol, 10.0equiv.). To the resulting solution cooled to 0° C. with an ice bath wasadded chloroacetyl chloride (131 μL, 1.64 mmol, 10.0 equiv.) dropwise.The ice bath was removed and the resulting mixture was stirred at r.t.for 30 min, diluted with DCM (20 mL), washed with saturated aqueousNaHCO₃ (15 mL), dried over sodium sulfate, and concentrated in vacuo. Tothe remaining residue was dissolved in ACN (3 mL) were added Et₃N (229μL, 1.64 mmol, 10.0 equiv.) and isopropyl amine (140 μL, 1.64 mmol, 10.0equiv.). The resulting solution was heated in a sealed tube at 100° C.in an oil bath for 45 minutes, cooled to r.t., concentrated underreduced pressure, and purified with reverse phase HPLC using 10%-100%ACN/water (both with 0.1% formic acid; Phenomenex Gemini C18 5 microncolumn) and by silica gel using 50% EA/Hex as eluent to provide 32 mg(46%) of6-(4-chlorobenzyl)-9-isopropyl-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane-3,7,10-trioneas a white solid. LRMS (APCI) m/z 427.2 (M+H). ¹H NMR (400 MHz,Methanol-d₄) δ 8.31-8.22 (m, 2H), 7.78 (ddd, J=8.5, 7.3, 2.0 Hz, 1H),7.20 (s, 4H), 7.13 (ddd, J=7.3, 4.9, 1.0 Hz, 1H), 4.98-4.89 (m, 1H),4.80-4.68 (m, 2H), 4.46 (d, J=12.4 Hz, 1H), 4.33-4.25 (m, 2H), 4.18 (d,J=17.8 Hz, 1H), 3.40 (d, J=17.8 Hz, 1H), 3.11 (d, J=17.8 Hz, 1H),1.30-1.22 (m, 6H).

Example 12: Synthesis of Compound 331

Method analogous to Example 11 was used with the exception thatiodobenzene was used in step 6 instead of 2-iodopyridine.

Example 13: Synthesis of Compound 330 1. Synthesis of Intermediate 13-1

To a solution of 1-(tert-butyl) 3-methyl3-((tert-butoxycarbonyl)amino)-2-oxopyrrolidine-1,3-dicarboxylate (437mg, 1.22 mmol) in DCM (5 mL) was added TFA (5 mL). The resulting mixturewas stirred at r.t. for 30 minutes, dried under reduced pressure andconcentrated to provide 330 mg (quantitative yield) of methyl3-amino-2-oxopyrrolidine-3-carboxylate as the TFA salt. LRMS (APCI) m/z159.1 (M+H).

2. Synthesis of Intermediate 13-2

To a mixture of methyl 3-amino-2-oxopyrrolidine-3-carboxylate TFA salt(330 mg, 1.22 mmol) and p-chlorobenzaldehyde (513 mg, 3.65 mmol, 3.0equiv.) in a mixture of dichloroethane (5 mL) and MeOH (5 mL) stirred atr.t. for 15 minutes was added NaBH₃CN (229 mg, 3.65 mmol, 3.0 equiv.).The resulting mixture was stirred at r.t. for 18 h. To the mixture wasadded additional p-chlorobenzaldehyde (513 mg, 3.65 mmol, 3.0 equiv.)and NaBH₃CN (229 mg, 3.65 mmol, 3.0 equiv.). The mixture was heated inan oil bath at 65° C. for 2 h, evaporated in vacuo, and partitionedbetween EA (40 mL) and saturated aqueous NaHCO₃ (40 mL). The layers wereseparated and the aqueous phase was extracted with additional EA (30mL). The organic phases were combined, dried over sodium sulfate,concentrated under reduced pressure, and purified with silica gelchromatography using a EA/Hex (0-100%) to provide 258 mg (75%) of methyl3-((4-chlorobenzyl)amino)-2-oxopyrrolidine-3-carboxylate. LRMS (APCI)m/z 283.1 (M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 7.37-7.15 (m, 4H), 3.74(d, J=12.4 Hz, 1H), 3.59 (d, J=12.4 Hz, 1H), 3.47-3.33 (m, 2H), 2.59(ddd, J=13.4, 7.3, 3.6 Hz, 1H), 2.23 (ddd, J=13.4, 8.7, 7.5 Hz, 1H).

3. Synthesis of Intermediate 13-3

To a mixture of CuI (6 mg, 0.033 mmol, 0.2 equiv.),4-iodo-1-methyl-1H-pyrazole (41 mg, 0.195 mmol, 1.2 equiv.) and K₂CO₃(90 mg, 0.651 mmol, 4.0 equiv.) were added methyl3-((4-chlorobenzyl)amino)-2-oxopyrrolidine-3-carboxylate (46 mg, 0.163mmol, 1.0 equiv.) in anhydrous 1,4-dioxane (2 mL) andN,N-dimethylethylenediamine (4 μL, 0.033 mmol, 0.2 equiv.). Theresulting mixture was flushed with nitrogen, sealed, heated in an oilbath at 115° C. for 18 h, cooled to room temperature, filtered through asyringe filter, and purified with reverse phase HPLC using 10%-100%ACN/water (both with 0.1% formic acid; Phenomenex Gemini C18 5 microncolumn) to provide 8 mg (14%) of methyl3-((4-chlorobenzyl)amino)-1-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrrolidine-3-carboxylate.LRMS (APCI) m/z 363.2 (M+H).

4. Synthesis of Compound 330

To a solution of methyl3-((4-chlorobenzyl)amino)-1-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrrolidine-3-carboxylate(8 mg, 0.022 mmol) in DCM (1 mL) was added Et₃N (31 μL, 0.22 mmol, 10.0equiv.). To the resulting solution cooled to 0° C. with an ice bath wasadded chloroacetyl chloride (18 μL, 0.22 mmol, 10.0 equiv.) dropwise andthe ice bath was removed upon the completion of addition. The resultingmixture was stirred at r.t. for 30 minutes, diluted with DCM (10 mL),washed once with saturated aqueous NaHCO₃ (10 mL), dried over sodiumsulfate, and concentrated in vacuo. The remaining residue was dissolvedin ACN (1 mL). To the mixture were added Et₃N (62 μL, 0.44 mmol, 20.0equiv.) and isopropyl amine (38 μL, 0.44 mmol, 20.0 equiv.)sequentially. The resulting solution was heated in a sealed tube at 100°C. in an oil bath for 45 min, cooled to r.t., evaporated under reducedpressure, and purified with reverse phase HPLC using 10%-100% ACN/water(both with 0.1% formic acid; Phenomenex Gemini C18 5 micron column) toprovide 5 mg (53%) of6-(4-chlorobenzyl)-9-isopropyl-2-(1-methyl-1H-pyrazol-4-yl)-2,6,9-triazaspiro[4.5]decane-1,7,10-trione.LRMS (APCI) m/z 430.2 (M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 7.91 (s,1H), 7.64 (s, 1H), 7.34-7.23 (m, 4H), 4.84 (d, J=16.1 Hz, 1H), 4.68 (p,J=6.9 Hz, 1H), 4.55 (d, J=16.1 Hz, 1H), 4.27 (d, J=17.7 Hz, 1H), 4.17(d, J=17.7 Hz, 1H), 3.93-3.83 (m, 4H), 3.70 (td, J=9.4, 2.6 Hz, 1H),2.82 (ddd, J=14.0, 8.4, 2.6 Hz, 1H), 2.57-2.45 (m, 1H), 1.23 (dd,J=10.0, 6.8 Hz, 6H).

Example 14: Synthesis of Compound 333

Method analogous to Example 13 was used with the exception that4-iodo-2-methylpyridine was used in step 4 instead of4-iodo-1-methyl-1H-pyrazole.

Example 15: Synthesis of Compound 389 1. Synthesis of Intermediate 15-2

To a solution of (S)-1-(4-chlorophenyl)ethan-1-amine (2.4 mL, 16.7 mmol,1.0 equiv) and tert-butyl 3-oxopyrrolidine-1-carboxylate (3.1 g, 16.7mmol, 1.0 equiv) in MeOH (16 mL) were added 2-isocyanopropane (1.6 mL,16.7 mmol, 1.0 equiv) and chloroacetic acid (1.6 g, 16.7 mmol, 1.0equiv). The mixture was stirred for 30 min, concentrated, and purifiedby silica gel chromatography to provide 3.2 g (39%) of tert-butyl3-(2-chloro-N—((S)-1-(4-chlorophenyl)ethyl)acetamido)-3-(isopropylcarbamoyl)pyrrolidine-1-carboxylateas a mixture of diastereomers. LRMS (ES) m/z 486.2 (M+H).

2. Synthesis of Intermediate 15-3

To a solution of tert-butyl3-(2-chloro-N—((S)-1-(4-chlorophenyl)ethyl)acetamido)-3-(isopropylcarbamoyl)pyrrolidine-1-carboxylate(3.2 g, 6.6 mmol, 1.0 equiv) in ACN (20 mL) was added potassiumcarbonate (0.9 g, 6.6 mmol, 2.0 equiv). The mixture was heated to 80° C.for 2 h, filtered, concentrated, and purified by silica gelchromatography (80 g, 0-100% EtOAc in hexanes) to provide 1.0 g (34%) oftert-butyl6-((S)-1-(4-chlorophenyl)ethyl)-9-isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2-carboxylateas a mixture of diastereomers. LRMS (ES) m/z 394.15 (M+H-^(t)Bu).

3. Synthesis of Intermediate 15-4

To a solution of tert-butyl6-((S)-1-(4-chlorophenyl)ethyl)-9-isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2-carboxylate(1.0 g, 2.2 mmol, 1.0 equiv) in DCM (5.0 mL) was added TFA (5 mL). Themixture was stirred for 20 min, concentrated, diluted with saturatedaqueous NaHCO₃ (200 mL), and layers were separated. The aqueous layerwas extracted with DCM three times. The combined organic washes weredried over MgSO₄, filtered, and concentrated, and purified by silica gelchromatography (24 g column, 0-40% MeOH in DCM) to provide 380 mg (49%)of6-4S)-1-(4-chlorophenyl)ethyl)-9-isopropyl-2,6,9-triazaspiro[4.5]decane-7,10-dioneas a mixture of diastereomers. LRMS (ES) m/z 350.2 (M+H).

4. Synthesis of Compound 389 (Diastereomers 389A and 389B

To a mixture of6-4S)-1-(4-chlorophenyl)ethyl)-9-isopropyl-2,6,9-triazaspiro[4.5]decane-7,10-dione(190 mg, 0.54 mmol, 1.0 equiv) and 2-fluoropyridine (132 mg, 1.4 mmol,2.5 equiv) in a microwave vial was added IPA (3 mL). The mixture washeated at 180° C. in the microwave reactor for 75 min, concentrated, andpurified by reverse phase HPLC (Phenomenex, gemini 5 uM C18 150×21.2 mm,10-100% acetonitrile in water both with 0.1% formic acid gradient over40 min) to provide 16 mg (14%) of the first eluting peak as Diastereomer389A and 15 mg of the second eluting peak as Diastereomer 389B.Diastereomer 389A characterization: LRMS (ES) m/z 427.1 (M+H). ¹H-NMR(Methanol-d₄, 400 MHz, ppm) δ 8.01 (ddd, J=5.3, 1.9, 0.9 Hz, 1H), 7.59(ddd, J=8.9, 7.1, 1.9 Hz, 1H), 7.29 (s, 4H), 6.69 (ddd, J=7.2, 5.2, 0.9Hz, 1H), 6.57 (dt, J=8.7, 0.9 Hz, 1H), 4.70 (p, J=6.9 Hz, 1H), 4.19-4.00(m, 3H), 3.83 (d, J=11.9 Hz, 2H), 3.60 (q, J=8.5 Hz, 1H), 2.73-2.52 (m,2H), 1.89 (d, J=6.9 Hz, 3H), 1.23 (dd, J=6.8, 2.1 Hz, 6H). Diastereomer389B characterization: LRMS (ES) m/z 427.1 (M+H). ¹H-NMR: (Methanol-d₄,400 MHz, ppm) δ 8.06 (ddd, J=5.2, 1.9, 0.8 Hz, 1H), 7.63 (ddd, J=8.8,7.1, 1.9 Hz, 1H), 7.37-7.27 (m, 4H), 6.73 (ddd, J=7.1, 5.3, 0.9 Hz, 1H),6.62 (d, J=8.6 Hz, 1H), 4.70 (p, J=6.9 Hz, 1H), 4.08 (d, J=2.6 Hz, 2H),4.02 (d, J=11.3 Hz, 1H), 3.92 (d, J=11.8 Hz, 1H), 3.71 (td, J=9.2, 4.0Hz, 1H), 3.60 (t, J=8.5 Hz, 1H), 2.77 (ddd, J=13.8, 8.2, 3.9 Hz, 1H),2.52 (dt, J=13.8, 8.3 Hz, 1H), 1.87 (d, J=6.9 Hz, 3H), 1.23 (dd, J=6.8,3.4 Hz, 6H).

The following compound was prepared by methods analogous to the methoddescribed for Compound 389:

Enantiomer No. LRMS (ES) m/z 504A M + H = 468.2

Example 16: Synthesis of Compound 367 1. Synthesis of Intermediate 16-2

To a solution of6-[(4-chlorophenyl)methyl]-9-(propan-2-yl)-2,6,9-triazaspiro[4.5]decane-7,10-dione(150 mg, 0.45 mmol, 1.00 equiv) in DCM (5 mL) at r.t were addedisocyanatotrimethylsilane (103 mg, 0.89 mmol, 2.00 equiv) and TEA (90mg, 0.89 mmol, 2.00 equiv). The mixture was stirred at r.t for 2 h,concentrated under reduced pressure, and purified by reverse phase-HPLCwith the following conditions [(2 #-AnalyseHPLC-SHIMADZU): Column,XBridge Prep OBD C18 Column, 5 um, 30*150 mm; mobile phase, Water (10mmol/L NH₄HCO₃) and ACN (22.0% ACN up to 35.0% in 8 min); Detector, UV220 nm] to give 105 mg (62%) of6-[(4-chlorophenyl)methyl]-7,10-dioxo-9-(propan-2-yl)-2,6,9-triazaspiro[4.5]decane-2-carboxamideas a white solid. LRMS (ES) m/z 379 (M+H). ¹H NMR (300 MHz, DMSO-d₆) δ7.40-7.28 (m, 2H), 7.16-7.07 (m, 2H), 5.77 (s, 2H), 4.69 (d, J=16.8 Hz,1H), 4.62-4.45 (m, 2H), 4.04 (d, J=2.8 Hz, 2H), 3.77 (d, J=11.7 Hz, 1H),3.34 (s, 1H), 3.27 (s, 2H), 2.20 (dt, J=8.8, 4.7 Hz, 2H), 1.09 (d, J=6.8Hz, 6H).

2. Separation of Compound 367

The racemic compound6-[(4-chlorophenyl)methyl]-7,10-dioxo-9-(propan-2-yl)-2,6,9-triazaspiro[4.5]decane-2-carboxamide(80 mg, 0.21 mmol, 1.00 equiv) was separated by Chiral-HPLC with thefollowing conditions (Column: CHIRALPAK IC, 2*25 cm, 5 um; Mobile PhaseA: Hex-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 16 mL/min; isocraticat 50% B for 28 min; 254/220 nm) to give 37.7 mg of the first elutedpeak as Enantiomer 367A and 33.2 mg of second eluted peak as Enantiomer367B. The chiral analytical data (CHIRALPAK IC-3; 0.46 cm×5 cm; 3micron; Hex (0.1% DEA):EtOH=50:50 at 1 ml/min) shows that the first peak(RT: 3.75 min) is Enantiomer 367A and second peak (RT: 4.61 min) isEnantiomer 367B.

Enantiomer 367A: LRMS (ES) m/z 379 (M+H). ¹HNMR (300 MHz, DMSO-d₆) δ7.40-7.30 (m, 2H), 7.16-7.07 (m, 2H), 5.77 (s, 2H), 4.69 (d, J=16.8 Hz,1H), 4.62-4.45 (m, 2H), 4.04 (d, J=2.8 Hz, 2H), 3.77 (d, J=11.7 Hz, 1H),3.34 (s, 1H), 3.27 (s, 2H), 2.26-2.14 (m, 2H), 1.09 (d, J=6.8 Hz, 6H).

Enantiomer 367B: LRMS (ES) m/z 379 (M+H). ¹HNMR (300 MHz, DMSO-d₆) δ7.40-7.30 (m, 2H), 7.17-7.07 (m, 2H), 5.77 (s, 2H), 4.69 (d, J=16.7 Hz,1H), 4.62-4.45 (m, 2H), 4.04 (d, J=2.8 Hz, 2H), 3.77 (d, J=11.7 Hz, 1H),3.34 (s, 1H), 3.27 (s, 2H), 2.20 (dt, J=8.9, 4.7 Hz, 2H), 1.09 (d, J=6.8Hz, 6H).

Example 17: Synthesis of Compound 347

To a solution of6-(5-(4-chlorobenzyl)-8-isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonan-2-yl)nicotinonitrile(100 mg, 0.236 mmol, 1.0 equiv) in THF (4 mL) at −78° C. was added LHMDS(1 M in THF, 354 μL, 0.35 mmol, 1.5 equiv) and chloromethyl methyl ether(38 mg, 0.47 mmol, 2.0 equiv) sequentially. The mixture was stirred for5 min at −78° C., warmed to r.t. over a period of 1 h, quenched withMeOH (0.5 mL), and purified by reverse phase HPLC (Phenomenex, gemini 5uC18 150×21.2 mm, 20-100% acetonitrile in water both with 0.1% formicacid gradient over 40 min) to provide 7.2 mg (7%) of6-(5-(4-chlorobenzyl)-8-isopropyl-7-(methoxymethyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonan-2-yl)nicotinonitrileas a white solid. LRMS (ES) m/z 468.2 (M+H). ¹H-NMR (Methanol-d₄, 400MHz, ppm) δ 8.38 (dd, J=2.2, 0.8 Hz, 1H), 7.77 (dd, J=8.8, 2.2 Hz, 1H),7.35-7.30 (m, 2H), 7.25 (d, J=8.6 Hz, 2H), 6.48 (dd, J=8.8, 0.9 Hz, 1H),5.12 (d, J=16.4 Hz, 1H), 4.75 (d, J=10.0 Hz, 1H), 4.40-4.31 (m, 2H),4.26 (d, J=10.2 Hz, 1H), 4.18-4.04 (m, 2H), 3.81 (dd, J=9.8, 1.7 Hz,1H), 3.74 (dd, J=9.8, 2.7 Hz, 1H), 3.40 (s, 3H), 1.40 (dd, J=6.8, 5.1Hz, 6H).

Example 18: Synthesis of Compound 348 1. Synthesis of Intermediate 18-2

To a solution of (4-Chlorophenyl)methanamine (0.27 g, 1.9 mmol, 1.0equiv) and tert-butyl 3-oxopyrrolidine-1-carboxylate (0.36 g, 1.9 mmol,1.0 equiv) in MeOH (5 mL) were added 1-isocyano-4-nitrobenzene (0.30 g,2.0 mmol, 1.05 equiv) and chloroacetic acid (0.18 g, 1.9 mmol, 1.0equiv). The mixture was stirred for 15 h at r.t., concentrated, andpurified by silica gel chromatography (0-100% EtOAc in hexanes) toprovide 200 mg of tert-butyl3-(2-chloro-N-(4-chlorobenzyl)acetamido)-3-((4-nitrophenyl)carbamoyl)pyrrolidine-1-carboxylate.LRMS (ES) m/z 495.1 (M+H-^(t)Bu).

2. Synthesis of Intermediate 18-3

To a solution of tert-butyl3-(2-chloro-N-(4-chlorobenzyl)acetamido)-3-((4-nitrophenyl)carbamoyl)pyrrolidine-1-carboxylate(200 mg, 0.36 mmol, 1.0 equiv) in IPA (5 mL) was added potassiumcarbonate (151 mg, 1.1 mmol, 3.0 equiv). The mixture was heated at 120°C. for 30 min, cooled to r.t., filtered, concentrated, and purified bysilica gel chromatography (0-100% EtOAc in hexanes) to providetert-butyl6-(4-chlorobenzyl)-9-(4-nitrophenyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2-carboxylate.LRMS (ES) m/z 459.1 (M+H-^(t)Bu).

3. Synthesis of Intermediate 18-4

To a solution of tert-butyl6-(4-chlorobenzyl)-9-(4-nitrophenyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2-carboxylate(0.36 mmol, 1.0 equiv assuming 100% yield) in DCM (2 mL) was added TFA(2 mL). The mixture was stirred for 20 min, concentrated, diluted withsaturated NaHCO₃ (200 mL), and extracted with DCM three times. Thecombined organic washes were dried over MgSO₄, filtered, andconcentrated to provide6-(4-chlorobenzyl)-9-(4-nitrophenyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione.This material was split into two equal portions and used in thesubsequent reaction. LRMS (ES) m/z 415.1 (M+H).

4. Synthesis of Compound 348

To a mixture of6-(4-chlorobenzyl)-9-(4-nitrophenyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione(0.18 mmol, 1.0 equiv), 5-cyano-2-fluoropyridine (33 mg, 0.27 mmol, 1.5equiv), and potassium carbonate (50 mg, 0.36 mmol, 2.0 equiv) in amicrowave tube was added IPA (3 mL). The mixture was sealed and heatedat 150° C. in the microwave reactor for 20 min, concentrated, andpurified by reverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm,20-100% acetonitrile in water both with 0.1% formic acid gradient over40 min) to provide 16 mg (17% over 3 steps) of6-(6-(4-chlorobenzyl)-9-(4-nitrophenyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]decan-2-yl)nicotinonitrileas a white foamy solid. LRMS (ES) m/z 517.0 (M+H). ¹H-NMR: (Methanol-d₄,400 MHz, ppm) δ 8.41-8.27 (m, 3H), 7.81-7.68 (m, 3H), 7.35-7.29 (m, 2H),7.28-7.20 (m, 2H), 6.49 (d, J=8.9 Hz, 1H), 4.99 (d, J=16.6 Hz, 1H),4.85-4.69 (m, 3H), 4.23 (d, J=12.6 Hz, 1H), 3.99 (d, J=12.6 Hz, 1H),3.79-3.58 (m, 2H), 2.79 (ddd, J=13.1, 8.2, 4.7 Hz, 1H), 2.68 (dt,J=13.6, 8.1 Hz, 1H).

Example 19: Synthesis of Compound 349

To a solution of6-(4-chlorobenzyl)-9-(4-nitrophenyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione(0.18 mmol, 1.0 equiv) in DCM (4 mL) were added TEA (55 mg, 0.54 mmol,3.0 equiv) and methyl isocyanate (31 mg, 0.54 mmol, 3.0 equiv). Themixture was stirred for 30 min, concentrated, and purified by reversephase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm, 20-100% acetonitrilein water both with 0.1% formic acid gradient over 40 min) to provide 17mg (20% over 3 steps) of6-(4-chlorobenzyl)-N-methyl-9-(4-nitrophenyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2-carboxamideas a white foamy solid. LRMS (ES) m/z 472.1 (M+H). (Methanol-d₄, 400MHz, ppm) δ 8.37-8.30 (m, 2H), 7.77-7.69 (m, 2H), 7.40-7.34 (m, 2H),7.32-7.28 (m, 2H), 4.92 (d, J=16.8 Hz, 1H), 4.81-4.63 (m, 3H), 4.09 (d,J=11.8 Hz, 1H), 3.72 (d, J=11.9 Hz, 1H), 3.47 (dd, J=8.1, 6.4 Hz, 2H),2.70 (s, 3H), 2.64-2.46 (m, 2H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 349:

Compound No. LRMS (ES) m/z 552 M + H = 500 559 M + H = 506 560 M + H =494 561 M + H = 508.1 562 M + H = 550.1 563 M + H = 480 564 M + H = 481565 M + H = 499 567 M + H = 481 568 M + H = 451 569 M + H = 530.9 570M + H = 499.1 571 M + H = 543 592 M + H = 514 615 M + H = 515

Example 20: Synthesis of Compound 350 1. Synthesis of Intermediate 20-2

To a mixture of ethyl3-((4-(trifluoromethyl)benzyl)amino)azetidine-3-carboxylate (1.53 g, 5.1mmol, 1.0 equiv) and 5-cyano-2-fluoropyridine (1.86 g, 15.2 mmol, 3.0equiv) in NMP (15 mL) was added diisopropylethylamine (4.4 mL, 25 mmol,5.0 equiv). The mixture was heated at 130° C. for 15 min, diluted withwater, and extracted with DCM three times. The combined extractions weredried over magnesium sulfate, filtered, concentrated, and purified bysilica gel chromatography (0-50% ethyl acetate in hexanes, gradient over26 min) to give 1.7 g (83%) of ethyl1-(5-cyanopyridin-2-yl)-3-((4-(trifluoromethyl)benzyl)amino)azetidine-3-carboxylateas a clear yellow oil. LRMS (ES) m/z 405 (M+H). ¹H NMR (400 MHz,Methylene Chloride-d₂) δ 8.43-8.41 (m, 1H), 7.69-7.61 (m, 3H), 7.59-7.53(m, 2H), 6.35-6.31 (m, 1H), 4.44-4.40 (m, 2H), 4.30 (q, J=7.1 Hz, 2H),4.13-4.07 (m, 2H), 3.87 (s, 2H), 1.34 (t, J=7.1 Hz, 3H).

2. Synthesis of Intermediate 20-3

To a solution of ethyl1-(5-cyanopyridin-2-yl)-3-((4-(trifluoromethyl)benzyl)amino)azetidine-3-carboxylate (1.7 g, 4.2 mmol, 1.0 equiv) in DCM (17mL) cooled to 0° C. were added TEA (3.6 mL, 25 mmol, 6.0 equiv) andchloroacetyl chloride (1.4 mL, 17 mmol, 4.0 equiv) dropwise. The mixturewas stirred at 0° C. for 30 min, diluted with saturated sodiumbicarbonate, and extracted with DCM three times. The combined organicextracts were dried over magnesium sulfate, filtered, concentrated, andpurified by silica gel chromatography (0-40% ethyl acetate in hexanes,gradient over 25 min) to give 2.1 g (100%) of ethyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-1-(5-cyanopyridin-2-yl)azetidine-3-carboxylateas a clear yellow oil. LRMS (ES) m/z 481 (M+H). ¹H NMR (400 MHz,Methylene Chloride-d₂) δ 8.38-8.35 (m, 1H), 7.70-7.66 (m, 3H), 7.53-7.48(m, 2H), 6.36-6.32 (m, 1H), 4.83-4.81 (m, 2H), 4.61-4.56 (m, 2H), 4.31(q, J=7.2 Hz, 2H), 4.27-4.21 (m, 2H), 4.01 (s, 2H), 1.31 (t, J=7.1 Hz,3H).

3. Synthesis of Intermediate 20-4

To a solution of ethyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-1-(5-cyanopyridin-2-yl)azetidine-3-carboxylate(214 mg, 0.45 mmol, 1.0 equiv) in a round-bottom flask was added ammonia(7 N in MeOH, 1.3 mL, 8.9 mmol, 20 equiv). The mixture was sealed,heated at 80° C. for 2 h, cooled to r.t., diluted with water, andextracted with EA three times. The combined organic extracts were driedover magnesium sulfate, filtered, concentrated, and purified by silicagel chromatography (0-10% MeOH/DCM, gradient over 11 min) to give 185 mg(quantitative) of6-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-2-yl)nicotinonitrileas a clear colorless oil. LRMS (ES) m/z 416 (M+H). ¹H NMR (400 MHz,Methylene Chloride-d₂) δ 8.43 (dd, J=2.2, 0.8 Hz, 1H), 7.69 (dd, J=8.7,2.2 Hz, 1H), 7.66-7.62 (m, 2H), 7.42-7.37 (m, 2H), 6.79 (s, 1H), 6.32(dd, J=8.7, 0.9 Hz, 1H), 5.09 (s, 2H), 4.69-4.63 (m, 2H), 4.28-4.23 (m,2H), 4.22-4.18 (m, 2H).

4. Synthesis of Compound 350

To a mixture of copper (I) iodide (10 mg, 0.06 mmol, 0.5 equiv) andpotassium carbonate (61 mg, 0.44 mmol, 4.0 equiv) in a flask which wasvacuum-nitrogen purged 3 times were added bromobenzene (0.017 mL, 0.16mmol, 1.5 equiv), N,N′-dimethylethylenediamine (0.006 mL, 0.06 mmol, 0.5equiv),6-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-2-yl)nicotinonitrile(46 mg, 0.11 mmol, 1.0 equiv), and dioxane (1 mL). The mixture was thenheated to 115° C. for 15 h, cooled to r.t, filtered, and purified byreverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm, 10-100%acetonitrile in water both with 0.1% formic acid gradient over 25 min)to give 12 mg (22%) of6-(6,9-dioxo-8-phenyl-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-2-yl)nicotinonitrileas a white solid. LRMS (ES) m/z 492 (M+H). ¹H NMR (400 MHz, Methanol-d₄)δ 8.38 (dd, J=2.2, 0.7 Hz, 1H), 7.77 (dd, J=8.8, 2.2 Hz, 1H), 7.69-7.64(m, 2H), 7.61-7.56 (m, 2H), 7.53-7.44 (m, 4H), 7.42-7.37 (m, 1H), 6.49(dd, J=8.8, 0.8 Hz, 1H), 5.19 (s, 2H), 4.71-4.66 (m, 2H), 4.58 (s, 2H),4.44-4.38 (m, 2H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 350:

Compound No. LRMS (ES) m/z 882 M + H = 482.0 883 M + H = 466.1 884 M + H= 500.0 885 M + H = 484.0 886 M + H = 507.0 887 M + H = 491.0

Example 21: Synthesis of Compound 334 1. Synthesis of Intermediate 21-2

To a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (1.26 g, 6.8mmol, 1.0 equiv) and 4-chlorobenzyl amine (0.96 g, 6.8 mmol, 1.0 equiv)in MeOH (15 mL) were added 4-methoxybenzylisocyanide (1.0 g, 6.8 mmol,1.0 equiv) and chloroacetic acid (0.64 g, 6.8 mmol, 1.0 equiv). Themixture was stirred for 2 h at r.t., diluted with EA, washed withsaturated sodium bicarbonate and saturated ammonium chloride, dried overmagnesium sulfate, filtered, concentrated, and purified by silica gelchromatography (0-30% ethyl acetate in hexanes, gradient over 25 min) togive 1.2 g (32%) of tert-butyl3-(2-chloro-N-(4-chlorobenzyl)acetamido)-3-((4-methoxybenzyl)carbamoyl)pyrrolidine-1-carboxylateas a white foam. LRMS (ES) m/z 494 (M+H-tertbutyl). ¹H NMR (400 MHz,Methylene Chloride-d₂) δ 7.41-7.37 (m, 2H), 7.25-7.18 (m, 4H), 6.92-6.87(m, 2H), 4.82-4.64 (m, 2H), 4.55-4.47 (m, 1H), 4.41-4.36 (m, 2H),4.08-4.02 (m, 1H), 4.01-3.96 (m, 1H), 3.82 (s, 3H), 3.54-3.48 (m, 1H),3.45-3.34 (m, 1H), 3.33-3.24 (m, 1H), 2.69-2.52 (m, 1H), 2.19-2.08 (m,1H), 1.44 (s, 9H).

2. Synthesis of Intermediate 21-3

To a solution of tert-butyl3-(2-chloro-N-(4-chlorobenzyl)acetamido)-3-((4-methoxybenzyl)carbamoyl)pyrrolidine-1-carboxylate(1.6 g, 2.9 mmol, 1.0 equiv) in THF (16 mL) cooled to 0° C. was addedLHMDS (1.0 M in THF, 9.0 mL, 8.6 mmol, 3.0 equiv) dropwise. The mixturewas stirred at 0° C. for 1 h, quenched with MeOH, concentrated, andpurified by silica gel chromatography (0-100% ethyl acetate in hexanes,gradient over 14 min) to give 54 mg (4%) of tert-butyl6-(4-chlorobenzyl)-9-(4-methoxybenzyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2-carboxylateas a clear colorless oil. ¹H NMR (400 MHz, Methylene Chloride-d₂) δ7.23-6.68 (m, 8H), 5.11-4.62 (m, 2H), 4.53-4.13 (m, 3H), 3.91-3.79 (m,1H), 3.69-3.57 (m, 3H), 3.51-3.22 (m, 3H), 2.43-1.95 (m, 2H), 1.39-1.20(m, 9H).

3. Synthesis of Intermediate 21-4

To a solution of tert-butyl6-(4-chlorobenzyl)-9-(4-methoxybenzyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2-carboxylate(0.055 g, 0.11 mmol, 1.0 equiv) in DCM (1 mL) was added TFA (0.080 mL,1.0 mmol, 10 equiv). The mixture was heated at 40° C. for 1 h,concentrated, and vacuum pump dried for 2 h to give 56 mg (quantitative)of6-(4-chlorobenzyl)-9-(4-methoxybenzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dioneas TFA salt. LRMS (ES) m/z 414 (M+H).

4. Synthesis of Compound 334

To a solution of6-(4-chlorobenzyl)-9-(4-methoxybenzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dioneTFA salt (56 mg 0.11 mmol, 1.0 equiv) in DCM (1 mL) cooled to 0° C. wereadded TEA (0.06 mL, 0.4 mmol, 4 equiv) and methyl isocyanate (9 mg, 0.2mmol, 1.5 equiv). The mixture was stirred at 0° C. for 30 min,concentrated, and purified by reverse phase HPLC (Phenomenex, gemini 5uC18 150×21.2 mm, 10-70% acetonitrile in water both with 0.1% formic acidgradient over 25 min) to give 46 mg (90%) of6-(4-chlorobenzyl)-9-(4-methoxybenzyl)-N-methyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2-carboxamideas a clear colorless oil. LRMS (ES) m/z 471 (M+H). ¹H NMR (400 MHz,Methanol-d₄) δ 7.36-7.31 (m, 2H), 7.29-7.23 (m, 2H), 7.20-7.14 (m, 2H),6.98-6.93 (m, 2H), 4.87-4.81 (m, 1H), 4.66-4.59 (m, 3H), 4.17-4.06 (m,2H), 3.98-3.93 (m, 1H), 3.82 (s, 3H), 3.63-3.58 (m, 1H), 3.55-3.44 (m,2H), 2.71 (s, 3H), 2.47-2.39 (m, 2H).

Example 22: Synthesis of Compound 202 1. Synthesis of Intermediate 22-2

To a solution of 1-tert-butyl 3-ethyl 3-aminoazetidine-1,3-dicarboxylate(20 g, 81.9 mmol, 1.0 equiv) in DCE (200 mL) were added4-(trifluoromethyl)benzaldehyde (15.7 g, 90.2 mmol, 1.10 equiv) and AcOH(9.8 g, 163.2 mmol, 2.0 equiv) at r.t. The mixture was stirred for 10min. To this mixture was added STAB (26 g, 122.676 mmol, 1.50 equiv) inportions. The mixture was stirred for 4 h, quenched with water (200 mL),and extracted with DCM (200 mL) twice. The combined organic layers werewashed with aqueous NaHCO₃ solution (200 mL) and brine (200 mL) twice,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give 33 g of 1-tert-butyl 3-ethyl3-([[4-(trifluoromethyl)phenyl]methyl]amino)azetidine-1,3-dicarboxylate(crude) as a yellow oil. LRMS (ES) m/z 347 (M+H-56).

2. Synthesis of Intermediate 22-3

To a mixture of 1-tert-butyl 3-ethyl3-([[4-(trifluoromethyl)phenyl]methyl]amino)azetidine-1,3-dicarboxylate(33 g, 82.005 mmol, 1 equiv) in DCM (300 mL) and K₂CO₃ (17 g, 123.0mmol, 1.50 equiv, 0.5) in water (246 mL) cooled to 0° C. was added2-bromoacetyl bromide (19.8 g, 98.1 mmol, 1.2 equiv) dropwise over aperiod of 15 min. The mixture was stirred at r.t. overnight andextracted with DCM (300 mL) twice. The combined organic layers werewashed with brine (300 mL) twice, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure to give 42 g (95%) of 1-tert-butyl3-ethyl3-(2-bromo-N-[[4-(trifluoromethyl)phenyl]methyl]acetamido)azetidine-1,3-dicarboxylateas a yellow oil. LRMS (ES) m/z 467 (M+H-56).

3. Synthesis of Intermediate 22-4

To 1-tert-butyl 3-ethyl3-(2-bromo-N-[[4-(trifluoromethyl)phenyl]methyl]acetamido)azetidine-1,3-dicarboxylate(42 g, 80.3 mmol, 1 equiv) in a round-bottom flask was added NH₃ in MeOH(7 M, 300 mL). The mixture was stirred at r.t. overnight, concentratedunder reduced pressure, and diluted with EtOAc (300 mL). The solid wascollected and dried to afford 29 g (87%) of tert-butyl6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-2-carboxylateas a white solid. LRMS (ES) m/z 358 (M+H-56).

4. Synthesis of Intermediate 22-5

To a solution of tert-butyl6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(33 g, 79.8 mmol, 1 equiv) in ACN (330 mL) at r.t were added3,4-difluorobenzonitrile (16.6 g, 119.3 mmol, 1.5 equiv) and Cs₂CO₃ (52g, 159.6 mmol, 2.0 equiv). The mixture was stirred at 80° C. for 2 days,cooled to r.t., and filtered to remove solids. The filtrate wasconcentrated under reduced pressure and purified by silica gel columnchromatography using EA/MeOH (7:3) as eluent and again with reversephase chromatography using ACN/water (gradient from 35-45% over 20 min)give 20 g (45%) of tert-butyl8-(4-carbamoyl-2-fluorophenyl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-2-carboxylateas an off-white solid. LRMS (ES) m/z 495 (M+H−56).

5. Synthesis of Intermediate 22-6

To a solution of tert-butyl8-(4-carbamoyl-2-fluorophenyl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(20 g, 36.3 mmol, 1 equiv) in DCM (200 mL) cooled at 0° C. were addedTEA (11 g, 108.7 mmol, 3.0 equiv) and TFAA (15 g, 71.4 mmol, 2.0 equiv).The mixture was stirred at r.t. overnight, quenched with water (200 mL),and extracted with DCM (200 mL) twice. The combined organic layers werewashed with brine (300 mL) twice, dried over anhydrous Na₂SO₄,concentrated under reduced pressure, purified by silica gelchromatography using PE/EtOAc (1:2) as eluent to afford 13 g (68%) oftert-butyl8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-2-carboxylateas a yellow oil. LRMS (ES) m/z 477 (M+H−56).

6. Synthesis of Intermediate 22-7

To a solution of tert-butyl8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(13 g, 24.4 mmol, 1 equiv) in DCM (120 mL) was added TFA (30 mL) at r.t.The mixture was stirred at r.t. for 4 h and concentrated under reducedpressure to give 10 g (98%) of4-(6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrileas TFA salt. LRMS (ES) m/z 433 (M+H).

7. Synthesis of Compound 202

To a solution of4-(6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile(10 g, 23.1 mmol, 1 equiv) in DCM (100 mL) at r.t were added acetylacetate (3.5 g, 34.3 mmol, 1.5 equiv) and TEA (7 g, 69.2 mmol, 3.0equiv). The mixture was stirred at r.t. for 3 h, quenched with water(100 mL), and extracted with DCM (100 mL) twice. The combined organiclayers were washed with brine (100 mL) twice, dried over anhydrousNa₂SO₄, concentrated under reduced pressure, and purified by reversephase chromatography using ACN/water (10 M NH₄HCO₃, gradient from 35-45%over 20 min) to give 7.8 g (70%) of4-(2-acetyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrileas an off-white solid. LRMS (ES) m/z 475 (M+H). ¹H-NMR: (400 MHz,Methanol-d₄, ppm) δ 7.83-7.77 (m, 1H), 7.77-7.67 (m, 4H), 7.57 (d, J=8.1Hz, 2H), 4.86 (s, 2H), 4.75-4.68 (m, 1H), 4.60-4.55 (m, 2H), 4.55-4.47(m, 2H), 4.25 (d, J=11.0 Hz, 1H), 1.87 (s, 3H).

Example 23: Synthesis of Compound 169 1. Synthesis of Intermediate 23-2

To a solution of 1-(tert-butyl)3-ethyl-3-aminoazetidine-1,3-dicarboxylate (6.0 g, 24.6 mmol, 1.0 equiv)in a mixture of THF (30 mL) and DCE (10 mL) was added4-trifluoromethylbenzaldehyde (6.4 g, 36.8 mmol, 1.5 equiv). The mixturewas stirred for 15 min. To this mixture were added STAB (26.0 g, 123mmol, 5.0 equiv) and AcOH (5 mL). The mixture was stirred for 2 h,evaporated under reduced pressure, and partitioned between DCM (60 mL)and saturated aqueous sodium bicarbonate (60 mL). The layers wereseparated and the aqueous phase was extracted with DCM (25 mL). Thecombined organic phases were dried over sodium sulfate, filtered throughcelite, concentrated under reduced pressure, and purified with silicagel chromatography using EtOAc/Hexanes (gradient from 0-100%), toprovide 9.4 g (95%) of 1-(tert-butyl) 3-ethyl3-((4-(trifluoromethyl)benzyl)amino)azetidine-1,3-dicarboxylate. LRMS(ES) m/z 347.1 (M+H-^(t)Bu).

2. Synthesis of Intermediate 23-3

To a solution of 1-(tert-butyl) 3-ethyl3-((4-(trifluoromethyl)benzyl)amino) azetidine-1,3-dicarboxylate (5.0 g,12.4 mmol, 1.0 equiv) in DCM (50 mL) at 0° C. were added TEA (8.7 mL,62.1 mmol, 5.0 equiv) and chloroacetyl chloride (4.0 mL, 49.7 mmol, 4.0equiv). The ice bath was removed and the mixture was stirred at R.T. for60 h before pouring into of saturated aqueous NH₄Cl (200 mL). The layerswere separated and the aqueous layer was extracted with DCM three times.The combined organic layers were dried over MgSO₄ and concentrated underreduced pressure to give 1-(tert-butyl) 3-ethyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)azetidine-1,3-dicarboxylate.The product was used directly in the next reaction without furtherpurification.

3. Synthesis of Intermediate 23-4

To a solution of 1-(tert-butyl) 3-ethyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)azetidine-1,3-dicarboxylate (5.75 g, 12.4 mmol) in a microwave vial wasadded 7 M NH₃ in MeOH (7 N, 30 mL). The mixture was sealed, heated at100° C. in the microwave reactor for 1 h, concentrated under reducedpressure, and purified by silica gel chromatography using EtOAc/hexanes9 gradient from 0-100%) and MeOH/DCM (isocratic at 20%) as eluent toprovide 3.6 g (70% over 2 steps) of tert-butyl6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylateas a white solid. LRMS (ES) m/z 358.1 (M+H-^(t)Bu). ¹H-NMR:(Methanol-d₄, 400 MHz, ppm) δ 7.68 (d, J=7.7 Hz, 2H), 7.50 (d, J=7.9 Hz,2H), 5.06 (s, 2H), 4.41 (d, J=9.7 Hz, 2H), 4.19-3.93 (m, 4H), 1.44 (s,9H).

Intermediate 23-4 has the same structure as Intermediate 22-4. In someembodiments, Intermediate 23-4 is prepared by following steps 1-3 inExample 22. In some embodiments, Intermediate 22-4 is prepared byfollowing steps 1-3 in Example 23.

4. Synthesis of Intermediate 23-5

To a mixture of copper iodide (12 mg, 0.06 mmol, 0.5 equiv), potassiumcarbonate (67 mg, 0.48 mmol, 4 equiv), 4-bromo-3-fluorobenzonitrile (36mg, 0.18 mmol, 1.5 equiv), and tert-butyl6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(50 mg, 0.12 mmol, 1.0 equiv) in a vial (3.0 mL) was added dioxane (1mL) and N,N′-dimethylethylene diamine (7 μL, 0.06 mmol, 0.5 equiv). Themixture was sealed in the vial, heated at 100° C. for 15 h, cooled tor.t., filtered, and concentrated under reduced pressure to givetert-butyl8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylatewhich was used in the next step without purification.

5. Synthesis of Intermediate 23-6

To a solution of tert-butyl8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(64 mg, 0.12 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture wasstirred at r.t. for 45 m and then concentrated to provide4-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrileas a glassy solid. The product was used in the next reaction withoutfurther purification.

6. Synthesis of Compound 169

To a solution of4-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile(52 mg, 0.12 mmol) in DCM (2 mL) were added TEA (0.5 mL) and methylisocyanate (15 mg, 0.26 mmol, 2.2 equiv) sequentially. The mixture wasstirred for 15 min, concentrated under reduced pressure, and purifiedwith reverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm, 10-100%acetonitrile in water with 0.1% formic acid gradient over 40 min) toprovide 15.6 mg (27% yield over 3 steps) of8-(4-cyano-2-fluorophenyl)-N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxamideas a white foamy solid. LRMS (ES) m/z 490.2 (M+H). ¹H-NMR: (Methanol-d₄,400 MHz, ppm) δ 7.82-7.77 (m, 1H), 7.75-7.67 (m, 4H), 7.57 (d, J=8.6 Hz,2H), 5.15 (s, 2H), 4.56 (s, 2H), 4.48 (d, J=9.5 Hz, 2H), 4.17 (d, J=9.5Hz, 2H), 2.68 (s, 3H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 169:

Compound No. LRMS (ES) m/z 145 M + H = 477.2 146 M + H = 472.1 147 M + H= 473.1 148 M + H = 505.1 149 M + H = 465.2 150 M + H = 481.1 151 M + H= 515.1 152 M + H = 483.2 153 M + H = 461.1 154 M + H = 478.2 155 M + H= 499.1 156 M + H = 482.1 157 M + H = 497.1 158 M + H = 487.2 159 M + H= 513.1 160 M + H = 531.1 161 M + H = 487.2 162 M + H = 490.1 163 M + H= 481.1 164 M + H = 438.1 165 M + H = 565.2 186 M + H = 457.1 187 M + H= 471.2 188 M + H = 473.1 189 M + H = 488.1 190 M + H = 443.1 191 M + H= 479.2 193 M + H = 497.2 194 M − H = 459.2 195 M + H = 506.1 196 Nomass signal 197 M + H = 475.1 198 M + H = 476.1 199 M + H = 516.2 200 Nomass product 201 M + H = 504.2 166 M + H = 495.1 167 M + H = 486.2 168M + H = 499.1 170 M + H = 495.1 171 M + H = 531.1 203 M + H = 501.1 204M + H = 476.1 172 M + H = 551.2 173 M + H = 530.2 174 M + H = 503.1 175M + H = 441.1 176 M + H = 425.1 177 M + H = 515.1 178 M + H = 529.2 179M + H = 461.1 180 M + H = 515.1 181 M + H = 555.1 182 M + H = 451.1 566M + H = 487 593 M + H = 521

Example 24: Synthesis of Compound 335 1. Synthesis of Intermediate 24-1

To a mixture of tert-butyl6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(50 mg, 0.12 mmol, 1.0 equiv) and 4-(trifluoromethyl)benzyl bromide (32mg, 0.13 mmol, 1.1 equiv) in DMF (1 mL) was added NaH (60% in mineraloil, 5 mg, 0.13 mmol, 1.1 equiv) at 0° C. The mixture was stirred at 0°C. for 30 min, quenched with water, and extracted with EA three times.The combined organic washes were dried over magnesium sulfate, filtered,concentrated, and purified by silica gel chromatography (0-100% ethylacetate in hexanes, gradient over 11 min) to give 33 mg (48%) oftert-butyl6,9-dioxo-5,8-bis(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylateas a clear colorless oil. LRMS (ES) m/z 516 (M+H-tert-butyl).

2. Synthesis of Intermediate 24-2

To a mixture of tert-butyl6,9-dioxo-5,8-bis(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(33 mg, 0.058 mmol, 1.0 equiv) in DCM (1 mL) was added TFA (0.10 mL, 1.3mmol, 22 equiv) at r.t. The mixture was heated at 40° C. for 2 h,concentrated, and vacuum pump dried to give 34 mg (100%) of 55,8-bis(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione2,2,2-trifluoroacetate as a clear yellow oil. LRMS (ES) m/z 472 (M+H).

3. Synthesis of Compound 335

To a solution of5,8-bis(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione2,2,2-trifluoroacetate (34 mg, 0.06 mmol, 1.0 equiv) in DCM (1 mL)cooled to 0° C. were added TEA (32 μL, 0.23 mmol, 4.0 equiv) and methylisocyanate (5 mg, 0.087 mmol, 1.5 equiv). The mixture was stirred at 0°C. for 30 min, concentrated, and purified by reverse phase HPLC(Phenomenex, gemini 5u C18 150×21.2 mm, 10-100% acetonitrile in waterboth with 0.1% formic acid gradient over 25 min) to give 21 mg (69%) ofN-methyl-6,9-dioxo-5,8-bis(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxamideas a white solid. LRMS (ES) m/z 529 (M+H). ¹H NMR (400 MHz, Methanol-d₄)δ 7.73-7.69 (m, 2H), 7.69-7.64 (m, 2H), 7.60-7.56 (m, 2H), 7.52-7.47 (m,2H), 5.08 (s, 2H), 4.79 (s, 2H), 4.48-4.43 (m, 2H), 4.14 (s, 2H),4.12-4.05 (m, 2H), 2.70 (s, 3H).

Example 25 Synthesis of Compound 192 1. Synthesis of Intermediate 25-1

To a mixture of tert-butyl6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(0.871 g, 2.11 mmol, 1.0 equiv), 4-bromobenzonitrile (0.575 g, 3.16mmol, 1.5 equiv), copper (I) iodide (0.201 g, 1.05 mmol, 0.50 equiv),and potassium carbonate (0.873 g, 6.32 mmol, 3.0 equiv) suspended inanhydrous 1,4-dioxane was added N,N-dimethylethylenediamine (0.11 mL,1.0 mmol, 0.50 equiv). The mixture was flushed with nitrogen, sealed,and heated at 100° C. for 15 h, cooled to r.t., filtered through celite,concentrated, and purified by silica gel chromatography usingEtOAc/Hexanes (gradient from 0-100%) to give 0.968 g (89%) of tert-butyl8-(4-cyanophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylateas a white foam. LRMS (ES) m/z 459 (M+H-tert-butyl).

2. Synthesis of Intermediate 25-2

To a solution of tert-butyl8-(4-cyanophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(0.968 g, 1.88 mmol, 1.0 equiv) in DCM (14 mL) was added TFA (1.4 mL, 19mmol, 10 equiv). The mixture was heated at 40° C. for 3 h, concentrated,diluted with saturated aqueous sodium bicarbonate, and extracted withethyl acetate three times. The combined organic layers were washed withbrine, dried over magnesium sulfate, and concentrated to give 0.751 g(96%) of4-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)benzonitrileas a white foam. LRMS (ES) m/z 415 (M+H). ¹H NMR (400 MHz, MethyleneChloride-d₂) δ 7.70-7.66 (m, 2H), 7.57-7.53 (m, 2H), 7.46-7.42 (m, 2H),7.38-7.34 (m, 2H), 5.19 (s, 2H), 4.34 (s, 2H), 4.31-4.24 (m, 2H),3.74-3.66 (m, 2H).

3. Synthesis of Compound 192

To a mixture of4-(6,9-Dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)benzonitrile(67 mg, 0.16 mmol, 1.0 equiv) and 5-cyano-2-fluoropyridine (0.024 g,0.19 mmol, 1.2 equiv) in DMF (1 mL) was added DIEA (0.042 mL, 0.24 mmol,1.5 equiv). The mixture was heated at 100° C. for 15 h, cooled to r.t.,and purified with reverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2mm, 10-100% acetonitrile in water both with 0.1% formic acid gradientover 25 min) to give 40 mg (48%) of6-(8-(4-cyanophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-2-yl)nicotinonitrileas a clear colorless oil. LRMS (ES) m/z 517 (M+H). ¹H NMR (400 MHz,Methanol-d₄) δ 8.38 (dd, J=2.2, 0.8 Hz, 1H), 7.89-7.83 (m, 2H), 7.77(dd, J=8.8, 2.2 Hz, 1H), 7.72-7.68 (m, 2H), 7.68-7.63 (m, 2H), 7.60-7.55(m, 2H), 6.49 (dd, J=8.8, 0.8 Hz, 1H), 5.18 (s, 2H), 4.71-4.66 (m, 2H),4.64 (s, 2H), 4.43-4.38 (m, 2H).

Example 26: Synthesis of Compound 336 1. Synthesis of Intermediate 26-1

To a mixture of tert-butyl6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(0.050 g, 0.12 mmol, 1.0 equiv) and 4-(bromomethyl)benzonitrile (25 mg,0.13 mmol, 1.1 equiv) in DMF (1 mL) at 0° C. was added NaH (60% inmineral oil, 5 mg, 0.13 mmol, 1.1 equiv) at 0° C. and then added 60%sodium hydride in mineral oil (0.005 g, 0.13 mmol, 1.1 equiv). Themixture was stirred at 0° C. for 30 min, quenched with water, andextracted with EA three times. The combined organic washes were driedover magnesium sulfate, filtered, concentrated, and purified by silicagel chromatography (0-100% ethyl acetate in hexanes, gradient over 11min) to give 55 mg (87%) of tert-butyl8-(4-cyanobenzyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylateas a clear colorless oil. LRMS (ES) m/z 473 (M+H-tert-butyl).

2. Synthesis of Intermediate 26-2

To a mixture of tert-butyl8-(4-cyanobenzyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(55 mg, 0.10 mmol, 1.0 equiv) in DCM (1 mL) was added TFA (0.10 mL, 1.3mmol, 12 equiv) at r.t. The mixture was heated at 40° C. for 2 h,concentrated, and vacuum pump dried to give 57 mg (100%) of4-((6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)methyl)benzonitrile2,2,2-trifluoroacetate as a clear yellow oil. LRMS (ES) m/z 429 (M+H).

3. Synthesis of Compound 336

To a solution of4-((6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)methyl)benzonitrile2,2,2-trifluoroacetate (57 mg, 0.10 mmol, 1.0 equiv) in DCM (1 mL)cooled to 0° C. were added TEA (59 μL, 0.42 mmol, 4.0 equiv) and methylisocyanate (9 mg, 0.087 mmol, 1.5 equiv). The mixture was stirred at 0°C. for 30 min, concentrated, and purified by reverse phase HPLC(Phenomenex, gemini 5u C18 150×21.2 mm, 10-80% acetonitrile in waterboth with 0.1% formic acid in 25 min) to give 32 mg (62%) of8-(4-cyanobenzyl)-N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxamideas a white solid. LRMS (ES) m/z 486 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ7.89-7.84 (m, 2H), 7.74-7.69 (m, 2H), 7.57-7.47 (m, 4H), 6.43-6.38 (m,1H), 4.94 (s, 2H), 4.69 (s, 2H), 4.28-4.20 (m, 2H), 4.08 (s, 2H),3.91-3.83 (m, 2H), 2.54-2.47 (m, 3H).

Example 27: Synthesis of Compound 338 1. Synthesis of Intermediate 27-1

To a solution of tert-butyl6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylateand 4-(1-bromoethyl)benzonitrile (50 mg, 0.12 mmol, 1.0 equiv) in DMF (1mL) at 0° C. was added NaH (5 mg of 60% dispersion in mineral oil, 0.13mmol, 1.1 equiv.). The resulting mixture was stirred at 0° C. for 1 h,quenched with addition of water (1 mL) dropwise, and extracted with EAthree times. The combined organic layers were washed with saturatedbrine, dried over magnesium sulfate, concentrated under reducedpressure, and purified with silica gel using a gradient from 0-100%EtOAc/hexanes to give 58 mg (88%) of tert-butyl8-(1-(4-cyanophenyl)ethyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylateas a clear colorless oil. LRMS (ES) m/z 487 (M+H-tertbutyl).

2. Synthesis of Intermediate 27-2

To a solution of tert-butyl8-(1-(4-cyanophenyl)ethyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(58 mg, 0.11 mmol, 1.0 equiv) in DCM (1 mL) was added trifluoroaceticacid (0.082 mL, 1.1 mmol, 10 equiv). The mixture was heated at 40° C.for 1 h and then concentrated under reduced pressure to give 59 mg(100%) of4-(1-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)ethyl)benzonitrile2,2,2-trifluoroacetate as a yellow oil. LRMS (ES) m/z 443 (M+H).

3. Synthesis of Compound 338

To a solution of4-(1-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)ethyl)benzonitrile2,2,2-trifluoroacetate (59 mg, 0.11 mmol, 1.0 equiv) in dry DCM (1 mL)at 0° C. were added TEA (59 μL, 0.42 mmol, 4.0 equiv) and methylisocyanate (9 mg, 0.16 mmol, 1.5 equiv). The mixture was stirred at 0°C. for 30 min, concentrated, and purified with reverse phase HPLC(Phenomenex, gemini 5u C18 150×21.2 mm, 10-80% acetonitrile in waterboth with 0.1% formic acid gradient over 25 min) to give 34 mg (63%) of8-(1-(4-cyanophenyl)ethyl)-N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxamideas a clear red oil. LRMS (ES) m/z 500 (M+H). ¹H NMR (400 MHz,Methanol-d₄) δ 7.81-7.76 (m, 2H), 7.69-7.64 (m, 2H), 7.63-7.58 (m, 2H),7.50-7.45 (m, 2H), 5.95 (q, J=7.1 Hz, 1H), 5.06 (s, 2H), 4.46-4.40 (m,2H), 4.21-4.13 (m, 1H), 4.11-4.03 (m, 2H), 3.74-3.65 (m, 1H), 2.69 (s,3H), 1.67 (d, J=7.2 Hz, 3H).

Example 28: Synthesis of Compound 216 1. Synthesis of Intermediate 28-2

This step followed the published method in Aust. J. Chem., 1993, 46,73-93 and Org. Biomol. Chem., 2010, 8, 5120-5125. (S)—S-methylcysteine(5.61 g, 41.5 mmol) was treated with a solution of NaOH (1.7 g, 41.5mmol, 1 equiv.) in water (25 mL) and after 5 minutes the resultinghomogeneous solution was evaporated to dryness under reduced pressure toprovide a white solid. To this mixture was added a solution ofpivaldehyde (5.35 g, 62.2 mmol, 1.5 equiv.) in hexanes (75 mL). Theresulting suspension was heated to reflux with stirring for 24 h with aDean-Stark trap to remove water. Refluxing was periodically interruptedto scrape solid material from the walls of the flask to facilitatestirring. After refluxing for 24 h, the reaction was evaporated todryness providing a white solid. To the white solid suspended in DCM (75mL) cooled to 0° C. with an ice bath was added benzyl chloroformate(8.88 mL, 62.2 mmol, 1.5 equiv.). The resulting mixture was stirred atr.t. for 36 h, quenched with saturated aqueous NaHCO₃ (50 mL), stirredfor 3 h, and the layers were separated. The aqueous phase was extractedwith DCM (50 mL). The combined organic phases were dried over sodiumsulfate, concentrated under reduced pressure, and purified with silicagel chromatography using EA/HE (1/9) as eluents to provide 3.0 g (21%)ofbenzyl(2R,4S)-2-(tert-butyl)-4-((methylthio)methyl)-5-oxooxazolidine-3-carboxylate(visualized with iodine) as a viscous colorless oil. LRMS (APCI) m/z338.2 (M+H). ¹H NMR (400 MHz, Chloroform-d) δ 7.35-7.28 (m, 5H), 5.48(s, 1H), 5.12 (d, J=1.7 Hz, 2H), 4.43 (dd, J=7.9, 5.7 Hz, 1H), 2.93 (dd,J=14.0, 8.0 Hz, 1H), 2.79 (dd, J=14.0, 5.7 Hz, 1H), 2.03 (s, 3H), 0.89(s, 9H).

2. Synthesis of Intermediate 28-3

To a solution of benzyl(2R,4S)-2-(tert-butyl)-4-((methylthio)methyl)-5-oxooxazolidine-3-carboxylate(2.95 g, 8.7 mmol) in DCM (100 mL) was added mCPBA (3.77 g, 21.8 mmol,2.5 equiv.). The resulting solution was stirred at r.t. for 18 h andquenched with saturated aqueous NaHCO₃ (150 mL). The aqueous phase wasextracted with DCM (50 mL). The combined organic phases were combined,dried over sodium sulfate, concentrated under reduced pressure, andpurified by silica gel chromatography using EA/Hex (1/3) as eluent toprovide 3.1 g (95%) of benzyl(2R,4S)-2-(tert-butyl)-4-((methylsulfonyl)methyl)-5-oxooxazolidine-3-carboxylate.LRMS (APCI) m/z 370.1 (M+H). ¹H NMR (400 MHz, Chloroform-d) δ 7.46-7.37(m, 5H), 5.65 (s, 1H), 5.34-5.20 (m, 2H), 5.01 (dd, J=8.0, 3.7 Hz, 1H),3.60 (dd, J=15.1, 8.0 Hz, 1H), 3.49-3.36 (m, 1H), 3.14 (s, 3H), 0.97 (s,9H).

3. Synthesis of Intermediate 28-4

This step was followed using the published method in Org. Biomol. Chem.,2010, 8, 5120-5125. To a solution of benzyl(2R,4S)-2-(tert-butyl)-4-((methylsulfonyl)methyl)-5-oxooxazolidine-3-carboxylate(3.05 g, 8.3 mmol) in DCM (50 mL) cooled to 0° C. with an ice bath wasadded DBU (1.36 mL, 9.1 mmol, 1.1 equiv.) dropwise. The resultingsolution was stirred at 0° C. for 30 min, diluted with water (50 mL),and the layers were separated. The organic phase was washed withadditional water (50 mL) twice, dried over sodium sulfate, concentratedunder reduced pressure, and purified through a short plug of silica gelusing EA/Hex (1/2) as eluents to provide 2.3 g (94%) of benzyl(R)-2-(tert-butyl)-4-methylene-5-oxooxazolidine-3-carboxylate as acolorless oil. LRMS (APCI) m/z 290.0 (M+H). ¹H NMR (400 MHz,Chloroform-d) δ 7.46-7.37 (m, 5H), 5.79-5.58 (m, 3H), 5.28 (d, J=1.5 Hz,2H), 0.96 (s, 9H).

4. Synthesis of Intermediate 28-5

This step followed the published method in Tetrahedron Letters, Vol. 33,No. 45, pp. 6755-6758, 1992 and Synthetic Communications, 25(9),1295-1302 (1995). To a solution of benzyl(R)-2-(tert-butyl)-4-methylene-5-oxooxazolidine-3-carboxylate (1.49 g,5.1 mmol) in DCM (25 mL) was addedN-(methoxymethyl)-N-(trimethylsilylmethyl) benzylamine (3.95 mL, 15.4mmol, 3 equiv.). To the resulting solution cooled to 0° C. with an icebath was added TFA (0.079 mL, 0.2 equivalents) dropwise. The mixture wasstirred at 0° C. for 5 min and the ice bath was removed. The mixture wasstirred at r.t. for 1 h, diluted with DCM (40 mL), washed with saturatedaqueous NaHCO₃ (50 mL), dried over sodium sulfate, concentrated underreduced pressure, and purified by silica gel chromatography using EA/HE(1/4) as eluents to provide 2.2 g (96%) of benzyl(2R,5S)-7-benzyl-2-(tert-butyl)-4-oxo-3-oxa-1,7-diazaspiro[4.4]nonane-1-carboxylate(2.20 g, 4.9 mmol, 96% yield) as a colorless, viscous oil. LRMS (APCI)m/z 423.3 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 7.45-7.32 (m, 5H),7.28-7.17 (m, 5H), 5.58 (s, 1H), 5.16 (d, J=12.1 Hz, 1H), 5.09 (d,J=12.2 Hz, 1H), 3.46 (s, 2H), 3.01-2.58 (m, 4H), 2.22 (t, J=6.5 Hz, 2H),0.83 (s, 9H).

5. Synthesis of Intermediate 28-6

To a solution of benzyl(2R,5S)-7-benzyl-2-(tert-butyl)-4-oxo-3-oxa-1,7-diazaspiro[4.4]nonane-1-carboxylate(2.18 g, 5.2 mmol) in MeOH (30 mL) was added NaOMe (2.8 mL of 25% inMeOH) dropwise at r.t. The resulting mixture was stirred at r.t. for 30min and diluted with EtOAc (200 mL), saturated NH₄Cl (100 mL) and water(100 mL). The layers were separated and the aqueous phase was extractedwith EtOAc (100 mL). The combined organic phases were washed with brine,dried over sodium sulfate, concentration under reduced pressure, andpurified by silica gel chromatography using EA/HE (1/1) as eluents toprovide 1.8 g (94%) of methyl(S)-1-benzyl-3-(((benzyloxy)carbonyl)amino)pyrrolidine-3-carboxylate asa colorless, sticky solid. LRMS (APCI) m/z 369.2 (M+H). ¹H NMR (400 MHz,Methanol-d₄) δ 7.37-7.18 (m, 10H), 5.04 (s, 2H), 3.73-3.43 (m, 5H), 3.12(d, J=10.7 Hz, 1H), 2.89 (d, J=10.7 Hz, 1H), 2.84-2.74 (m, 1H), 2.61(dt, J=9.3, 7.1 Hz, 1H), 2.40 (ddd, J=13.2, 7.4, 5.6 Hz, 1H), 2.05 (dt,J=13.6, 7.0 Hz, 1H).

6. Synthesis of Intermediate 28-7

To a solution of methyl(S)-1-benzyl-3-(((benzyloxy)carbonyl)amino)pyrrolidine-3-carboxylate(1.78 g, 4.8 mmol) in MeOH (25 mL) were added concentrated HCl (0.150mL) and palladium (5% on carbon, 300 mg). The resulting mixture wassparged with hydrogen for 30 minutes and then stirred at r.t. underhydrogen (1 atm) for 18 h. The reaction mixture was filtered throughcelite and the filtrate was concentrated under reduced pressure toprovide 691 mg (61%) of methyl (S)-3-aminopyrrolidine-3-carboxylatedihydrogen chloride as a sticky salt. LRMS (APCI) m/z 145.1 (M+H). ¹HNMR (400 MHz, Methanol-d₄) δ 3.73 (s, 3H), 3.42-3.31 (m, 2H), 3.28-3.20(m, 1H), 3.03 (d, J=11.9 Hz, 1H), 2.29 (dt, J=13.3, 8.5 Hz, 1H), 1.92(td, J=8.0, 3.9 Hz, 1H).

7. Synthesis of Intermediate 28-8

To a solution of methyl (S)-3-aminopyrrolidine-3-carboxylate dihydrogenchloride (631 mg, 2.9 mmol) in DCM (20 mL) were added TEA (3.1 mL, 22.0mmol, 7.6 equiv.) and (Boc)₂O (960 mg, 4.4 mmol, 1.5 equiv.) in DCM (5mL). The resulting solution was stirred at r.t. for 15 min, quenchedwith diethylamine (0.453 mL, 4.4 mmol, 1.5 equiv.), stirred at r.t. for15 min, washed with saturated aqueous NaHCO₃ (25 mL), dried over sodiumsulfate, concentrated, and purified by silica gel chromatography usingEA/HE (gradient from 0-100%) to provide 656 mg (61%) of 1-(tert-butyl)3-methyl (S)-3-aminopyrrolidine-1,3-dicarboxylate. LRMS (APCI) m/z 189.1(M+H)−C₄H₉). ¹H NMR (400 MHz, Methanol-d₄) δ 3.77 (s, 3H), 3.72 (dd,J=11.2, 4.4 Hz, 1H), 3.53 (dq, J=8.4, 4.6, 3.7 Hz, 2H), 3.32-3.31 (m,1H), 2.33 (dq, J=12.8, 8.2 Hz, 1H), 2.00-1.88 (m, 1H), 1.48 (s, 9H).

8. Synthesis of Intermediate 28-9

To a mixture of 1-(tert-butyl) 3-methyl(S)-3-aminopyrrolidine-1,3-dicarboxylate (1.20 g, 4.91 mmol) andp-trifluoromethylbenzaldehyde (1.71 g, 9.8 mmol, 2.0 equiv.) in amixture of THF (30 mL) and DCE (10 mL) was added HOAc (1 mL). To theresulting mixture stirred at r.t. for 5 min was added STAB (5.21 g,24.56 mmol, 5.0 equiv.). The mixture was continued to stir at r.t. for48 h, evaporated under reduced pressure, and partitioned between DCM(150 mL) and saturated NaHCO₃ (60 mL). The aqueous phase was extractedwith DCM (25 mL). The combined organic phases were dried over sodiumsulfate, and concentrated under reduced pressure, and purified by silicagel chromatography using EA/Hex (1/4) as eluents to provide 1.2 g (62%)of 1-(tert-butyl) 3-methyl(S)-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-1,3-dicarboxylate.LRMS (APCI) m/z 403.1 (M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 7.61 (d,J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 3.90-3.79 (m, 1H), 3.79-3.65 (m,5H), 3.55 (qd, J=8.3, 7.9, 4.2 Hz, 1H), 3.50-3.40 (m, 2H), 2.37-2.26 (m,1H), 2.09 (ddt, J=12.0, 7.5, 3.7 Hz, 1H), 1.46 (d, J=20.4 Hz, 9H).

9. Synthesis of Intermediate 28-10

To a mixture of 1-(tert-butyl) 3-methyl(S)-3-((4-(trifluoromethyl)benzyl)amino) pyrrolidine-1,3-dicarboxylate(1.20 g, 2.98 mmol) and TEA (6.24 mL, 44.73 mmol, 15.0 equiv.) in DCM(50 mL) cooled to 0° C. was added chloroacetylchloride (3.37 g, 29.82mmol, 10.0 equiv.) dropwise using a syringe. Upon completion of theaddition, the ice bath was removed. The resulting brown suspension wasstirred at r.t. for 1.5 h, diluted with DCM (75 mL), and washed withsaturated aqueous NaHCO₃ (75 mL). The organic phase was dried oversodium sulfate, concentrated, and purified by silica gel chromatographyusing EA/Hex (4/6) as eluents to provide 0.92 g (64%) of 1-(tert-butyl)3-methyl(S)-3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine-1,3-dicarboxylateas.LRMS (APCI) m/z 379.2 (M+H with Boc loss). ¹H NMR (400 MHz, Methanol-d₄)δ 7.75 (d, J=8.1 Hz, 2H), 7.63 (d, J=6.9 Hz, 2H), 5.02 (d, J=19.3 Hz,1H), 4.85 (d, 1H), 4.34-4.16 (m, 3H), 3.78 (s, 3H), 3.53-3.42 (m, 1H),3.40-3.33 (m, 2H), 2.46-2.21 (m, 2H), 1.46 (d, J=4.3 Hz, 9H).

10. Synthesis of Intermediate 28-11

To 1-(tert-butyl) 3-methyl (S)-3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine-1,3-dicarboxylate (0.90 g. 1.88 mmol) was addedNH₃ in MeOH (7 M, 25 mL). The mixture was sealed, heated at 80° C. for1.5 h, cooled down to r.t., evaporated under reduced pressure, andpartitioned between DCM (100 mL) and water (50 mL). The aqueous phasewas extracted with DCM (25 mL). The combined organic phases were driedover sodium sulfate, concentrated, and purified by silica gelchromatography using EA/Hex (gradient from 0-100% and 100%) as eluentsto provide 0.72 g (89%) of tert-butyl(S)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate.LRMS (APCI) m/z 372.1 (M+H) (—C₄H₉). ¹H NMR (400 MHz, Methanol-d₄) δ7.66 (d, J=7.9 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 5.01 (dd, J=33.8, 17.0Hz, 1H), 4.69 (dd, J=37.6, 17.1 Hz, 1H), 4.18 (d, J=4.5 Hz, 2H),3.95-3.84 (m, 1H), 3.61-3.46 (m, 3H), 2.49-2.33 (m, 2H), 1.42 (d, J=24.0Hz, 9H).

11. Synthesis of Intermediate 28-12

To a mixture of tert-butyl(S)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate(280 mg, 0.63 mmol), CuI (60 mg, 0.32 mmol, 0.5 equiv.), K₂CO₃ (349 mg,2.53 mmol, 4.0 equiv.) and aryl iodide (234 mg, 0.95 mmol, 1.5 equiv.)in 1,4-dioxane (6 mL) was added N,N-dimethylethylenediamine (0.034 mL,0.32 mmol, 0.5 equiv.). The resulting mixture was heated at 115° C.under N₂ for 18 h in a sealed tube, cooled to r.t., filtered throughcelite, washed with additional dioxane (15 mL) and DCM (30 mL),concentrated under reduced pressure, and purified by silica gelchromatography using EA/Hex (1/1) as eluents to provide 187 mg (54%) oftert-butyl(S)-9-(4-cyano-2-fluorophenyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate.LRMS (APCI) m/z 491.1 (M+H) (—C₄H₉). ¹H NMR (400 MHz, Methanol-d₄) δ7.82-7.64 (m, 5H), 7.50 (d, J=8.0 Hz, 2H), 5.15-5.02 (m, 1H), 4.81-4.57(m, 3H), 4.00 (d, J=12.1 Hz, 1H), 3.66 (d, J=12.3 Hz, 1H), 3.62-3.47 (m,2H), 2.59-2.48 (m, 2H), 1.43 (d, J=15.3 Hz, 9H).

12. Synthesis of Intermediate 28-13

To a solution of tert-butyl(S)-9-(4-cyano-2-fluorophenyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate(186 mg, 0.34 mmol) in DCM (3 mL) was added TFA (3 mL). The resultingmixture was stirred at r.t. for 30 min and concentrated under reducedpressure to provide 189 mg (99%) of(S)-4-(7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decan-9-yl)-3-fluorobenzonitrileas a TFA salt. LRMS (APCI) m/z 447.1 (M+H).

13. Synthesis of Compound 216

To a mixture of(S)-4-(7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decan-9-yl)-3-fluorobenzonitrile(30 mg TFA salt, 0.054 mmol) and DIEA (0.047 mL, 0.27 mmol, 5.0 equiv.)in DCM (1.0 mL) was added methyl chloroformate (0.012 mL, 0.16 mmol, 3.0equiv.). The mixture was stirred at r.t. for 5 min, evaporated underreduced pressure, and purified with reverse phase HPLC using 10-100%ACN/water (both with 0.1% formic acid; Phenomenex Gemini C18 5 microncolumn) to provide 21 mg (78%) of methyl(S)-9-(4-cyano-2-fluorophenyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate(21 mg, 0.042 mmol, 78% yield, Compound 216) as a white amorphous solid.LRMS (APCI) m/z 505 (M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 7.84-7.65 (m,5H), 7.49 (d, J=8.0 Hz, 2H), 5.05 (dt, J=9.5, 5.2 Hz, 1H), 4.87-4.73 (m,1H), 4.73-4.56 (m, 2H), 4.05 (d, J=12.2 Hz, 1H), 3.76-3.48 (m, 6H),2.64-2.45 (m, 2H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 216:

Compound No. LRMS (ES) m/z 183 M + H = 486.1 184 M + H = 487.2 185 M + H= 452.1 205 M + H = 455.1 206 M + H = 455.1 207 M + H − Boc = 413.1 208M + H − Boc = 447.1 209 M + H = 489.2 210 M + H = 497.2 211 M + H =471.1 212 M + H = 495.2 213 M + H = 481.2 214 M + H = 469.1 215 M + H =531.2 217 M + H = 529.2 218 M + H = 503.2 219 M + H = 515.2 220 M + H =441.1 221 M + H = 483.2 222 M + H = 475.1 223 M + H = 517.2 224 M + H =478.1 225 M + H = 443.2

Example 29: Synthesis of Compound 211

Method analogous to Example 28 was used with the only exception thatp-chlorobenzaldehyde was used in step 8 instead of p-CF₃ benzaldehyde.

Example 30: Synthesis of Compound 320 1. Synthesis of Intermediate 30-2

To a solution of 1-(tert-butyl)3-ethyl-3-aminoazetidine-1,3-dicarboxylate (5.0 g, 20.5 mmol, 1.0 equiv)in a mixture of THF (50 mL) and DCE (10 mL) was added4-trifluoromethylbenzaldehyde (5.3 g, 30.7 mmol, 1.5 equiv). To themixture was stirred for 15 min were added STAB (13.0 g, 61.4 mmol, 3.0equiv) and AcOH (5 mL). The mixture was stirred at r.t. for 2 h,evaporated under reduced pressure, and partitioned between DCM (60 mL)and saturated aqueous sodium bicarbonate (60 mL). The layers wereseparated and the aqueous phase was extracted with DCM (25 mL). Thecombined organic phases were dried over sodium sulfate, filtered throughcelite, concentrated under reduced pressure, and purified by silica gelchromatography (gradient from 0-100% EtOAc/Hexanes) to provide1-(tert-butyl) 3-ethyl3-((4-(trifluoromethyl)benzyl)amino)azetidine-1,3-dicarboxylate. LRMS(ES) m/z 347.15 (M+H-^(t)Bu).

2. Synthesis of Intermediate 30-3

To a solution of 1-(tert-butyl) 3-ethyl3-((4-(trifluoromethyl)benzyl)amino) azetidine-1,3-dicarboxylate (20.5mmol, 1.0 equiv) in DCM (50 mL) at 0° C. were added TEA (14.3 mL, 102mmol, 5.0 equiv) and chloroacetyl chloride (3.3 mL, 40.9 mmol, 2.0equiv). The ice bath was removed and the mixture was stirred at r.t. for2 h before pouring into saturated aqueous NH₄Cl (200 mL). The layerswere separated and the aqueous layer was extracted with DCM (100 mL)three times. The combined organic layers were dried over MgSO₄,concentrated, and purified by silica gel chromatography (gradient from0-100% EtOAc/Hexanes) to give 8.2 g (84% over 2 steps) of 1-(tert-butyl)3-ethyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)azetidine-1,3-dicarboxylateas an off-white solid. LRMS (ES) m/z 479.15 (M+H).

3. Synthesis of Intermediate 30-4

To a solution of 1-(tert-butyl) 3-ethyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)azetidine-1,3-dicarboxylate (0.20 g, 0.42 mmol, 1.0 equiv) inACN (2 mL) in a microwave vial were added 3-aminobutanenitrilehydrochloride (76 mg, 0.63 mmol, 1.5 equiv) and TEA (175 μL, 1.3 mmol,3.0 equiv). The mixture was heated at 110° C. in the microwave reactorfor 1 h. The mixture containing tert-butyl8-(1-cyanopropan-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylatewas used directly in the next step. LRMS (ES) m/z 481.1 (M+H).

4. Synthesis of Intermediate 30-5

To the mixture containing tert-butyl8-(1-cyanopropan-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(202 mg, 0.42 mmol) in DCM was added TFA (2 mL). The mixture was stirredat r.t. for 20 minutes and concentrated to provide3-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)butanenitrile2,2,2-trifluoroacetate. LRMS (ES) m/z 381.1 (M+H).

5. Synthesis of Compound 320

To a solution of3-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)butanenitrile2,2,2-trifluoroacetate (160 mg, 0.42 mmol) in DCM (3 mL) were added TEA(0.5 mL) and methyl isocyanate (200 mg, 3.5 mmol, 8.3 equiv). Themixture was stirred at r.t. for 20 min, evaporated under reducedpressure, and purified with reverse phase HPLC (Phenomenex, gemini 5uC18 150×21.2 mm, 10-70% acetonitrile in water both with 0.1% formic acidgradient over 40 min) to provide 6.8 mg (4% over 3 steps) of8-(1-cyanopropan-2-yl)-N-methyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxamide.LRMS (ES) m/z 438.1 (M+H). ¹H-NMR: (Methanol-d₄, 400 MHz, ppm) δ 7.66(d, J=8.0 Hz, 2H), 7.50 (d, J=8.6 Hz, 2H), 5.22-5.01 (m, 2H), 4.87-4.75(m, 1H), 4.44 (dd, J=17.3, 9.3 Hz, 2H), 4.18 (d, J=1.6 Hz, 2H), 4.07(dd, J=9.3, 0.6 Hz, 2H), 2.98 (dd, J=17.1, 8.6 Hz, 1H), 2.86 (dd,J=17.1, 6.1 Hz, 1H), 2.68 (s, 3H), 1.40 (d, J=6.9 Hz, 3H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 320:

Compound No. LRMS (ES) m/z 518A M + H = 464.2 516A M + H = 452.2 323 M +H = 466.2 324 M + H = 488.2 520A M + H = 463.2 326 M + H = 452.2

Example 31: Synthesis of Compound 429B 1. Synthesis of Intermediate 31-1

To a mixture of 4-trifluoromethylbenzyl amine (1.8 g, 10.4 mmol, 1.0equiv) and tert-butyl 3-oxocyclobutane-1-carboxylate (1.8 g, 10.4 mmol,1.0 equiv) in MeOH (30 mL) were added (isocyanomethylene)dibenzene (2.1g, 10.9 mmol, 1.05 equiv) and chloroacetic acid (1.0 g, 10.4 mmol, 1.05equiv). The mixture was stirred at r.t. for 15 h, concentrated underreduced pressure, and purified by silica gel chromatography EA/HE(gradient from 0-100%) to provide 4.5 g (70%) of tert-butyl3-(benzhydrylcarbamoyl)-3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxylate(Intermediate 1-1). LRMS (ES) m/z 615.2 (M+H).

2. Synthesis of Diastereomer 31-2A and Diastereomer 31-2B

To a solution of tert-butyl3-(benzhydrylcarbamoyl)-3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxylate(Intermediate 31-1) (4.5 g, 7.3 mmol, 1.0 equiv) in THF (20 mL) cooledto 0° C. with an ice bath was added LiHMDS (1 M in THF, 8.8 mmol, 1.2equiv) dropwise over 10 min. The mixture was stirred at 0° C. for 2 h,quenched with MeOH (5 mL), concentrated onto SiO₂ (20 g), and purifiedby silica gel chromatography using EA/HE (gradient from 0-100%) toprovide the corresponding diastereomers. Diastereomer 31-2A (1.8 g,42%), diastereomer 31-2B (1.8 g, 42%).

Characterization of Diastereomer 31-2A: LRMS (ES) m/z 579.2 (M+H).¹H-NMR (Methanol-d₄, 400 MHz, ppm) δ 7.60-7.48 (m, 2H), 7.35-7.24 (m,8H), 7.17-7.06 (m, 4H), 6.89 (s, 1H), 4.76 (s, 2H), 3.76 (s, 2H),2.88-2.76 (m, 1H), 2.68-2.46 (m, 4H), 1.29 (s, 9H).

Characterization of Diastereomer 31-2B: LRMS (ES) m/z 579.2 (M+H).¹H-NMR (Methanol-d₄, 400 MHz, ppm) δ 7.49 (d, J=7.9 Hz, 2H), 7.34-7.25(m, 6H), 7.21 (d, J=7.9 Hz, 2H), 7.13-7.07 (m, 4H), 6.88 (s, 1H), 4.86(s, 2H), 3.68 (s, 2H), 3.01-2.79 (m, 3H), 2.59-2.40 (m, 2H), 1.32 (s,9H).

Diastereomer 31-2B was used in the subsequent examples. The finalcompounds derived from Diastereomer 31-2A were isolated usingDiastereomer 31-2A as the starting material in an analogous sequence.

3. Synthesis of Intermediate 31-3B

To a solution of Diastereomer 31-2B (1.8 g, 3.1 mmol, 1.0 equiv) inEtOAc (20 mL) was added Pd(OH)₂ (20% on carbon, 2 g). The mixture wassparged with hydrogen for 10 min, heated at 60° C. under hydrogen(initially at 700 psi) for 24 h, cooled to r.t., filtered throughcelite, concentrated under reduced pressure, and purified by silica gelchromatography using MeOH/DCM (gradient from 0-20%) to give 1.0 g (78%)of Intermediate 31-3B. LRMS (ES) m/z 357.1 (M+H-^(t)Bu). ¹H-NMR:(Methanol-d₄, 400 MHz, ppm) δ 7.67 (d, J=8.0 Hz, 2H), 7.44 (d, J=7.9 Hz,2H), 5.04 (s, 2H), 4.04 (s, 2H), 3.16-3.02 (m, 1H), 3.02-2.86 (m, 2H),2.73-2.59 (m, 2H), 1.46 (s, 9H). As used in this example, the dashedbond --- indicates that the stereochemical configuration of the startingmaterial is retained in the product compound.

4. Synthesis of 429B

To a mixture of copper iodide (109 mg, 0.57 mmol, 0.5 equiv), potassiumcarbonate (0.32 g, 2.3 mmol, 2.0 equiv), 4-bromo-3-fluorobenzonitrile(0.27 g, 1.4 mmol, 1.2 equiv), and Intermediate 1-3B (0.47 g, 1.1 mmol,1.0 equiv) in a vial were added 1,4-dioxane (5 mL) andN,N′-dimethylethylene diamine (61 μl, 0.57 mmol, 0.5 equiv). The mixturewas sealed and heated at 100° C. for 4 h, cooled to r.t., filteredthrough celite, and purified by silica gel chromatography using EA/HE(gradient from 0-100%) to provide 0.40 g (66%) of Compounds 429B. LRMS(ES) m/z 476.1 (M+H-^(t)Bu). ¹H-NMR (Methanol-d₄, 400 MHz, ppm) δ7.80-7.74 (m, 1H), 7.71-7.66 (m, 4H), 7.53-7.46 (m, 2H), 5.10 (s, 2H),4.50 (s, 2H), 3.15-2.99 (m, 3H), 2.85-2.71 (m, 2H), 1.42 (s, 9H).

Example 32: Synthesis of Compound 486B 1. Synthesis of Intermediate32-1B

To a flask containing Compound 429B (0.36 g, 0.68 mmol, 1.0 equiv) wasadded TFA (5 mL). The mixture was stirred at r.t. for 15 h andconcentrated to provide Intermediate 32-1B. LRMS (ES) m/z 474.1 (M−H).As used in this example, the dashed bond --- indicates that thestereochemical configuration of the starting material is retained in theproduct compound.

2. Synthesis of Intermediate 32-2B

To Intermediate 32-1B (0.32 g, 0.68 mmol, 1.0 equiv) dissolved in DCM (5mL) were added oxalyl chloride (0.17 g, 1.36 mmol, 2.0 equiv) and a dropof DMF (˜50 mg). The mixture was stirred at r.t. for 1 h andconcentrated to provide Intermediate 32-2B which was used directlywithout characterization.

3. Synthesis of Compound 486B

To Intermediate 32-2B (50 mg, 0.10 mmol, 1.0 equiv) dissolved in DCM (3mL) was added methylamine (2 M in THF, 2 mL). The mixture was stirred atr.t. for 1 h and concentrated. This material was dissolved in DMF (2.0mL), filtered, and purified with reverse phase HPLC (Phenomenex, gemini5u C18 150×21.2 mm, 20-100% acetonitrile in water both with 0.1% formicacid gradient over 25 min) to give 31.4 mg (64%) of Compound 486B. LRMS(ES) m/z 489.1 (M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 7.78-7.74 (m, 1H),7.72-7.65 (m, 4H), 7.50-7.45 (m, 2H), 5.12 (s, 2H), 4.49 (s, 2H),3.18-3.07 (m, 3H), 2.78-2.67 (m, 5H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 486B:

Diastereomer No. LRMS (ES) m/z ¹H NMR 429B M + H-^(t)Bu = 476.1 (400MHz, Methanol-d₄) δ 7.78-7.64 (m, 5H), 7.53-7.47 (m, 2H), 5.06 (s, 2H),4.50 (s, 2H), 2.99-2.89 (m, 1H), 2.87-2.79 (m, 2H), 2.75-2.67 (m, 2H),1.40 (s, 9H) 429A M + H = 532.2 (400 MHz, Methanol-d₄) δ 7.77-7.72 (m,1H), 7.70-7.64 (m, 4H), 7.50-7.45 (m, 2H), 5.09 (s, 2H), 4.48 (s, 2H),3.12-3.01 (m, 3H), 2.81-2.71 (m, 2H), 1.40 (s, 9H) 485A M + H = 475.1(400 MHz, Methanol-d₄) δ 7.81-7.76 (m, 1H), 7.75-7.69 (m, 2H), 7.68-7.63(m, 2H), 7.51-7.45 (m, 2H), 5.15 (s, 2H), 4.51 (s, 2H), 3.10-2.99 (m,1H), 2.82-2.76 (m, 4H) 485B M + H = 475.1 (400 MHz, Methanol-d₄) δ7.78-7.73 (m, 1H), 7.71-7.64 (m, 4H), 7.51-7.46 (m, 2H), 5.12 (s, 2H),4.49 (s, 2H), 3.22-3.08 (m, 3H), 2.79-2.68 (m, 2H) 486B M + H = 489.1(400 MHz, Methanol-d₄) δ 7.78-7.74 (m, 1H), 7.72-7.65 (m, 4H), 7.50-7.45(m, 2H), 5.12 (s, 2H), 4.49 (s, 2H), 3.18-3.07 (m, 3H), 2.78-2.67 (m,5H) 487A M + H = 503.2 (400 MHz, Methanol-d₄) δ 7.80-7.76 (m, 1H),7.76-7.69 (m, 2H), 7.68-7.63 (m, 2H), 7.50-7.45 (m, 2H), 5.07 (s, 2H),4.52 (s, 2H), 3.38-3.27 (m, 1H), 2.94 (s, 3H), 2.92 (s, 3H), 2.88-2.76(m, 4H) 486A M + H = 489.2 (400 MHz, Methanol-d₄) δ 7.80-7.75 (m, 1H),7.74-7.68 (m, 2H), 7.68-7.64 (m, 2H), 7.51-7.46 (m, 2H), 5.18 (s, 2H),4.51 (s, 2H), 3.04-2.93 (m, 1H), 2.84-2.68 (m, 7H) 487B M + H = 503.2(400 MHz, Methanol-d₄) δ 7.78-7.73 (m, 1H), 7.72-7.64 (m, 4H), 7.54-7.48(m, 2H), 5.15 (s, 2H), 4.50 (s, 2H), 3.29-3.09 (m, 3H), 2.87 (s, 3H),2.83 (s, 3H), 2.78-2.69 (m, 2H) 877A M + H = 485 (400 MHz, DMSO-d6) δ8.52 (d, J = 2.1 Hz, 1H), 8.29 (dd, J = 9.5, 2.2 Hz, 1H), 7.72 (d, J =8.1 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.38 (s, 1H), 6.89 (s, 1H), 5.04(s, 2H), 4.57 (s, 2H), 2.95-2.82 (m, 1H), 2.67-2.56 (m, 4H).

Example 33: Synthesis of Compound 444B 1. Synthesis of Intermediate 33-1

To a mixture of 4-trifluoromethylbenzyl amine (3.2 g, 18.4 mmol, 1.0equiv) and tert-butyl 3-oxocyclobutane-1-carboxylate (3.1 g, 18.4 mmol,1.0 equiv) in MeOH (30 mL) were added (isocyanomethylene)dibenzene (3.7g, 19.3 mmol, 1.05 equiv) and chloroacetic acid (1.8 g, 19.3 mmol, 1.05equiv). The mixture was stirred at r.t. for 15 h, concentrated underreduced pressure, and purified by silica gel chromatography EA/HE(gradient from 0-100%) to provide 10.5 g (93%) of ten-butyl3-(benzhydrylcarbamoyl)-3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxylate(Intermediate 33-1). LRMS (ES) m/z 615.25 (M+H).

2. Synthesis of Diastereomer 33-2B

To a solution of ten-butyl3-(benzhydrylcarbamoyl)-3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxylate(Intermediate 33-1) (10.5 g, 17.1 mmol, 1.0 equiv) in THF (200 mL)cooled to 0° C. with an ice bath was added LHMDS (1 M in THF, 20.5 mmol,1.2 equiv) dropwise over 10 min. The mixture was stirred at 0° C. for 2h, and MeOH was added (5 mL), concentrated onto Sift (20 g), andpurified by silica gel chromatography using EA/HE (gradient from 0-100%)to provide the corresponding diastereomers. Diastereomer 33-2A((discarded), diastereomer 33-2B (3.0 g, 30%).

Characterization of Diastereomer 33-2B: LRMS (ES) m/z 579.2 (M+H).¹H-NMR (Methanol-d₄, 400 MHz, ppm) δ 7.49 (d, J=7.9 Hz, 2H), 7.34-7.25(m, 6H), 7.21 (d, J=7.9 Hz, 2H), 7.13-7.07 (m, 4H), 6.88 (s, 1H), 4.86(s, 2H), 3.68 (s, 2H), 3.01-2.79 (m, 3H), 2.59-2.40 (m, 2H), 1.32 (s,9H).

3. Synthesis of Intermediate 33-3B

To a solution of Diastereomer 33-2B (3.0 g, 5.2 mmol, 1.0 equiv) inEtOAc (80 mL) was added Pd(OH)₂ (20% on carbon, 6 g). The mixture wassparged with hydrogen for 10 min, heated at 60° C. under hydrogen(initially at 500 psi) for 24 h, cooled to r.t., filtered throughcelite, concentrated under reduced pressure, and purified by silica gelchromatography using MeOH/DCM (gradient from 0-20%) to give 1.75 g (82%)of Intermediate 33-3B. LRMS (ES) m/z 357.1 (M+H-^(t)Bu). ¹H-NMR:(Methanol-d₄, 400 MHz, ppm) δ 7.67 (d, J=8.0 Hz, 2H), 7.44 (d, J=7.9 Hz,2H), 5.04 (s, 2H), 4.04 (s, 2H), 3.16-3.02 (m, 1H), 3.02-2.86 (m, 2H),2.73-2.59 (m, 2H), 1.46 (s, 9H). As used in this example, the dashedbond --- indicates that the stereochemical configuration of the startingmaterial is retained in the product compound.

4. Synthesis of Intermediate 33-4B

To a mixture of copper iodide (369 mg, 1.9 mmol, 0.5 equiv), potassiumcarbonate (1.6 g, 11.6 mmol, 3.0 equiv), 4-bromo-3-fluorobenzonitrile(1.4 g, 7.0 mmol, 1.8 equiv), and Intermediate 33-3B (1.6 g, 3.9 mmol,1.0 equiv) in vial were added 1,4-dioxane (16 mL) andN,N′-dimethylethylene diamine (209 μL, 1.9 mmol, 0.5 equiv). The mixturewas sealed and heat at 100° C. for 15 h, cooled to r.t., filteredthrough celite, and purified by silica gel chromatography using EA/HE(gradient from 0-100%) to provide 1.7 g (84%) of Intermediate 33-4B.LRMS (ES) m/z 476.1 (M+H-^(t)Bu). (CD₂Cl₂, 400 MHz, ppm) δ 7.70-7.65 (m,2H), 7.63-7.60 (m, 1H), 7.60-7.56 (m, 1H), 7.56-7.51 (m, 1H), 7.44-7.39(m, 2H), 5.02 (s, 2H), 4.40-4.38 (m, 2H), 3.19-3.11 (m, 2H), 3.03-2.94(m, 1H), 2.70-2.62 (m, 2H), 1.42 (s, 9H).

5. Synthesis of Intermediate 33-5B

To a solution of Intermediate 1-4B (1.7 g, 3.3 mmol, 1.0 equiv) in DCM(18 mL) was added TFA (18 mL). The mixture was stirred at r.t. for 1 hand concentrated to provide Intermediate 33-5B. LRMS (ES) m/z 474.0(M−H).

6. Synthesis of Compound 444B

To a mixture of morpholine (9.0 mg, 0.10 mmol, 1.0 equiv), PyBroP (49mg, 0.10 mmol, 1.0 equiv), and Intermediate 33-5B (50 mg, 0.10 mmol, 1.0equiv) in DCM (1 mL) cooled to 0° C. with an ice bath was added DIEA(0.073 mL, 0.42 mmol, 4.0 equiv) dropwise. The mixture was warmed tor.t., stirred for 30 min, concentrated under reduce pressure, andpurified with reverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm,10-80% acetonitrile in water both with 0.1% formic acid gradient over 25min) to give a mixture, which was purified again by silica gelchromatography using MeOH/DCM (1/9) to give 26.4 mg (46%) of Compound444B. LRMS (ES) m/z 545 (M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 7.81-7.75(m, 1H), 7.74-7.66 (m, 4H), 7.55-7.49 (m, 2H), 5.15 (s, 2H), 4.52 (s,2H), 3.65-3.57 (m, 4H), 3.55-3.49 (m, 2H), 3.31-3.14 (m, 5H), 2.81-2.72(m, 2H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 444B:

Diastereomer No. LRMS (ES) m/z ¹H NMR 446B M + H = 515.2 (400 MHz,Methanol-d₄) δ 7.80-7.76 (m, 1H), 7.73-7.66 (m, 4H), 7.56-7.50 (m, 2H),5.15 (s, 2H), 4.51 (s, 2H), 4.06-3.94 (m, 4H), 3.19-3.11 (m, 2H),3.06-2.95 (m, 1H), 2.73-2.64 (m, 2H), 2.33-2.23 (m, 2H) 448B M + H =529.2 (400 MHz, Methanol-d₄) δ 7.80-7.76 (m, 1H), 7.75-7.67 (m, 4H),7.60-7.49 (m, 2H), 5.20-5.13 (m, 2H), 4.54-4.50 (m, 2H), 3.52-3.41 (m,1H), 3.29-3.20 (m, 2H), 2.88-2.79 (m, 3H), 2.79-2.71 (m, 2H), 2.61-2.53(m, 1H), 0.80-0.69 (m, 2H), 0.69-0.58 (m, 2H) 450B M + H = 559.2 (400MHz, Methanol-d₄) δ 7.80-7.75 (m, 1H), 7.74-7.67 (m, 4H), 7.56-7.50 (m,2H), 5.23-5.09 (m, 2H), 4.57-4.46 (m, 2H), 4.04-3.95 (m, 1H), 3.86-3.77(m, 1H), 3.51-3.42 (m, 1H), 3.30-3.01 (m, 5H), 2.81-2.71 (m, 2H),1.85-1.77 (m, 2H), 1.45-1.34 (m, 2H) 452B M + H = 531.1 (400 MHz,Methanol-d₄) δ 7.81-7.75 (m, 1H), 7.73-7.66 (m, 4H), 7.53-7.48 (m, 2H),5.14 (s, 2H), 4.95-4.80 (m, 3H), 4.55-4.49 (m, 4H), 3.21-3.09 (m, 3H),2.84-2.72 (m, 2H) 458B M + H = 515.10 (400 MHz, Methanol-d₄) δ 7.80-7.75(m, 1H), 7.73-7.66 (m, 4H), 7.51-7.45 (m, 2H), 5.12 (s, 2H), 4.50 (s,2H), 3.16-3.04 (m, 3H), 2.77-2.66 (m, 2H), 2.64-2.56 (m, 1H), 0.71-0.64(m, 2H), 0.48-0.42 (m, 2H) 462B M + H = 545.1 (400 MHz, Methanol-d₄) δ7.80-7.75 (m, 1H), 7.74-7.66 (m, 4H), 7.52-7.46 (m, 2H), 5.14 (s, 2H),4.51 (s, 2H), 4.39-4.31 (m, 1H), 4.30-4.21 (m, 1H), 3.19-3.07 (m, 3H),2.80-2.67 (m, 2H), 2.28-2.16 (m, 4H) 469B M + H = 519.2 (400 MHz,Methanol-d₄) δ 7.80-7.75 (m, 1H), 7.73-7.67 (m, 4H), 7.52-7.47 (m, 2H),5.14 (s, 2H), 4.51 (s, 2H), 3.57 (t, J = 5.8 Hz, 2H), 3.28 (t, J = 5.8Hz, 2H), 3.23-3.09 (m, 3H), 2.82-2.70 (m, 2H) 473B M + H = 565.1 (400MHz, Methanol-d₄) δ 7.80-7.75 (m, 1H), 7.73-7.67 (m, 4H), 7.52-7.47 (m,2H), 5.14 (s, 2H), 4.51 (s, 2H), 4.13-4.02 (m, 1H), 3.19-3.07 (m, 3H),2.94-2.81 (m, 2H), 2.81-2.70 (m, 2H), 2.59-2.43 (m, 2H) 477B M + H =545.2 (400 MHz, Methanol-d₄) δ 7.80-7.75 (m, 1H), 7.74-7.66 (m, 4H),7.56-7.50 (m, 2H), 5.24-4.67 (m, 7H), 4.54-4.49 (m, 2H), 3.36-2.91 (m,6H), 2.84-2.73 (m, 2H) 462A M + H = 545 (400 MHz, Methanol-d₄) δ7.81-7.75 (m, 1H), 7.73-7.66 (m, 4H), 7.52-7.46 (m, 2H), 5.14 (s, 2H),4.51 (s, 2H), 3.98-3.89 (m, 1H), 3.82-3.70 (m, 1H), 3.20-3.06 (m, 3H),2.78-2.67 (m, 2H), 2.67-2.58 (m, 2H), 1.84-1.74 (m, 2H). 249B M + H =529 (400 MHz, Methanol-d₄) δ 7.80-7.75 (m, 1H), 7.72-7.66 (m, 4H),7.51-7.47 (m, 2H), 5.14 (s, 2H), 4.50 (s, 2H), 4.30-4.19 (m, 1H),3.20-3.06 (m, 3H), 2.77-2.65 (m, 2H), 2.29-2.18 (m, 2H), 1.99-1.85 (m,2H), 1.76-1.61 (m, 2H). 878B M + H = 481.0 (400 MHz, Methanol-d₄) δ 8.41(s, 1H), 7.90 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz,2H), 5.18 (s, 2H), 4.65 (br, 1H), 4.39 (br, 1H), 3.08 (p, J = 8.7 Hz,1H), 2.82 (s, 4H), 2.30 (s, 3H). 879B M + H = 467 (400 MHz, Methanol-d₄)δ 8.49 (d, J = 2.5 Hz, 1H), 8.11 (d, J = 8.9 Hz, 1H), 7.91 (dd, J = 8.9,2.5 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 5.14(s, 2H), 4.80 (s, 2H), 3.05 (p, J = 8.7 Hz, 1H), 2.80 (p, J = 11.4 Hz,4H).

Example 34: Synthesis of Compound 463B 1. Synthesis of Intermediate34-1B

To a mixture of triethylamine (0.070 mL, 0.51 mmol, 1.2 equiv) anddiphenyl phosphoryl azide (0.10 mL, 0.46 mmol, 1.1 equiv) in tert-butylalcohol (1.3 mL) was added Intermediate 33-5B (0.20 g, 0.42 mmol, 1.0equiv). The mixture was warmed to 83° C. and stirred for 15 hoursovernight. The reaction was diluted with water and extracted three timeswith DCM. The DCM extracts were combined, dried over MgSO₄, filtered,evaporated, and purified by silica gel chromatography using EA inhexanes (0-100% gradient) to give 94 mg (48%) of Intermediate 34-1B. ¹HNMR (400 MHz, Methylene Chloride-d₂) δ 7.71-7.66 (m, 2H), 7.66-7.63 (m,1H), 7.63-7.59 (m, 1H), 7.57-7.50 (m, 1H), 7.46-7.39 (m, 2H), 4.99 (s,2H), 4.49-4.37 (m, 3H), 3.05-2.88 (m, 2H), 2.79-2.70 (m, 2H). As used inthis example, the dashed bond --- indicates that the stereochemicalconfiguration of the starting material is retained in the productcompound.

2. Synthesis of Compound 463B

To Intermediate 34-1B (32 mg, 0.067, 1.0 equiv) in dry dichloromethane(1 mL) were added diisopropylethylamine (0.035 mL, 0.20 mmol, 3.0 equiv)followed by methylamine (2.0 M/THF, 0.10 mL, 0.20 mmol, 3.0 equiv). Themixture was stirred for 15 minutes at r.t., evaporated, and purified byreverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm, 10-80%acetonitrile in water with 0.1% formic acid in 25 min) to give 15 mg(45%) of compound 463B. LRMS (ES) m/z 504.1 (M+H). ¹H NMR (400 MHz,Methanol-d₄) δ 7.81-7.77 (m, 1H), 7.74-7.66 (m, 4H), 7.52-7.46 (m, 2H),5.12 (s, 2H), 4.51 (s, 2H), 4.41-4.31 (m, 1H), 2.97-2.89 (m, 2H),2.79-2.71 (m, 2H), 2.66 (s, 3H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 463B:

Diastereomer No. LRMS (ES) m/z ¹H NMR 463B M + H = 504.1 (400 MHz,Methanol-d₄) δ 7.81-7.77 (m, 1H), 7.74-7.66 (m, 4H), 7.52-7.46 (m, 2H),5.12 (s, 2H), 4.51 (s, 2H), 4.41-4.31 (m, 1H), 2.97-2.89 (m, 2H),2.79-2.71 (m, 2H), 2.66 (s, 3H) 465B M + H = 530.1 (400 MHz,Methanol-d₄) δ 7.82-7.77 (m, 1H), 7.75-7.66 (m, 4H), 7.53-7.47 (m, 2H),5.12 (s, 2H), 4.52 (s, 2H), 4.44-4.34 (m, 1H), 3.02-2.92 (m, 2H),2.78-2.70 (m, 2H), 2.45-2.38 (m, 1H), 0.70-0.64 (m, 2H), 0.46-0.40 (m,2H) 467B M + H = 546.1 (400 MHz, Methanol-d₄) δ 7.82-7.77 (m, 1H),7.75-7.66 (m, 4H), 7.52-7.46 (m, 2H), 5.11 (s, 2H), 4.85-4.75 (m, 3H),4.52 (s, 2H), 4.51-4.45 (m, 2H), 4.39-4.30 (m, 1H), 2.99-2.89 (m, 2H),2.78-2.70 (m, 2H)

Example 35: Synthesis of Compound 454B 1. Synthesis of Intermediate35-1B

To a solution of Intermediate 33-5B (0.25 g, 0.53 mmol, 1.0 equiv) in amixture of DCM (10 mL) and MeOH (10 mL) was added TMSCHN₂ (2 M inhexanes, 0.79 mL, 3.0 equiv). The mixture was stirred at r.t. for 2 hand concentrated to provide Intermediate 35-1B. LRMS (ES) m/z 490.1(M+H). As used in this example, the dashed bond --- indicates that thestereochemical configuration of the starting material is retained in theproduct compound.

2. Synthesis of Intermediate 35-2B

To a solution of Intermediate 35-1B (259 mg, 0.53 mmol, 1.0 equiv) inMeOH (5 mL) was added NH₂NH₂ (35% in water, 1 mL). The mixture washeated at 70° C. for 2 h, cooled to r.t., concentrated under reducedpressure, and purified by silica gel chromatography using MeOH/DCM (1/4)to provide 75 mg (29% over 2 steps) of Intermediate 35-2B. LRMS (ES) m/z490.2 (M+H). ¹H-NMR: (Methanol-d₄, 400 MHz, ppm) δ 7.76-7.71 (m, 1H),7.67-7.61 (m, 4H), 7.44 (d, J=8.1 Hz, 2H), 5.09 (s, 2H), 4.46 (s, 2H),3.17-3.02 (m, 3H), 2.78-2.62 (m, 2H), 1.87 (s, 2H).

3. Synthesis of Compound 454B

To a solution of Intermediate 35-2B (25 mg, 0.051 mmol, 1.0 equiv) inTHF (1 mL) were added TEA (0.2 mL) and difluoro acetic anhydride (13 mg,0.077 mmol, 1.5 equiv). The resulting mixture was heated at 120° C. in amicrowave for 20 minutes and purified with reverse phase HPLC(Phenomenex, gemini 5u C18 150×21.2 mm, 10-80% acetonitrile in waterboth with 0.1% formic acid gradient over 40 min) to provided 10.2 mg(36%) of Compound 454B. LRMS (ES) m/z 550.1 (M+H). ¹H-NMR: (Methanol-d₄,400 MHz, ppm) δ 7.80-7.74 (m, 1H), 7.74-7.66 (m, 4H), 7.54 (d, J=8.1 Hz,2H), 7.09 (t, J=51.7 Hz, 1H), 5.20 (s, 2H), 4.55 (s, 2H), 3.92 (dq,J=10.8, 6.0, 5.4 Hz, 1H), 3.39-3.28 (m, 2H), 3.16 (dd, J=14.1, 10.5 Hz,2H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 454B:

Diastereomer No. LRMS (ES) m/z ¹H NMR 430B M + H = 500.1 (400 MHz,Methanol-d₄) δ 8.82 (s, 1H), 7.77-7.72 (m, 1H), 7.71-7.66 (m, 4H),7.54-7.49 (m, 2H), 5.19 (s, 2H), 4.52 (s, 2H), 3.92-3.81 (m, 1H),3.38-3.26 (m, 2H), 3.15-3.06 (m, 2H) 440B M + H = 514.2 (400 MHz,Methanol-d₄) δ 7.80-7.75 (m, 1H), 7.73-7.66 (m, 4H), 7.55-7.51 (m, 2H),5.20 (s, 2H), 4.54 (s, 2H), 3.86-3.75 (m, 1H), 3.31-3.25 (m, 2H),3.13-3.04 (m, 2H), 2.48 (s, 3H)

Example 36: Synthesis of Compound 432B 1. Synthesis of Intermediate36-1B

To a solution of Intermediate 33-5B (100 mg, 0.21 mmol, 1.0 equiv) inDMF (2 mL) were added HATU (88 mg, 0.23 mmol, 1.1 equiv), acetamidinehydrochloride (30 mg, 0.32 mmol, 1.5 equiv), and TEA (106 mg, 1.1 mmol,5.0 equiv). The mixture was stirred at r.t. for 15 h to provideintermediate 36-1B, which was used directly in the next step. LRMS (ES)m/z 516.1 (M+H). As used in this example, the dashed bond --- indicatesthat the stereochemical configuration of the starting material isretained in the product compound.

2. Synthesis of Compound 432B

To the DMF solution containing 36-1B were added hydroxylaminehydrochloride (100 mg, 1.44 mmol, 6.9 equiv) and AcOH (2 mL). Theresulting mixture was heated at 80° C. for 2 h, concentrated underreduced pressure, and purified with reverse phase HPLC (Phenomenex,gemini 5u C18 150×21.2 mm, 20-100% acetonitrile in water both with 0.1%formic acid gradient over 40 min) to provide 15.3 mg (14% over 2 steps)of compound 432B. LRMS (ES) m/z 514.1 (M+H). (Methanol-d₄, 400 MHz, ppm)δ 7.77-7.73 (m, 1H), 7.72-7.64 (m, 4H), 7.54-7.49 (m, 2H), 5.18 (s, 2H),4.52 (s, 2H), 3.87-3.77 (m, 1H), 3.34-3.24 (m, 2H), 3.14-3.05 (m, 2H),2.30 (s, 3H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 432B:

Diastereomer No. LRMS (ES) m/z ¹H NMR 432B M + H = 514.1 (400 MHz,Methanol-d₄) δ 7.77-7.73 (m, 1H), 7.72-7.64 (m, 4H), 7.54-7.49 (m, 2H),5.18 (s, 2H), 4.52 (s, 2H), 3.87-3.77 (m, 1H), 3.34-3.24 (m, 2H),3.14-3.05 (m, 2H), 2.30 (s, 3H) 434B M + H = 544.1 (400 MHz,Methanol-d₄) δ 7.79-7.74 (m, 1H), 7.74-7.66 (m, 4H), 7.56-7.51 (m, 2H),5.20 (s, 2H), 4.94-4.83 (m, 1H), 4.54 (s, 2H), 3.91-3.81 (m, 1H),3.40-3.29 (m, 2H), 3.17-3.09 (m, 2H), 1.49 (d, J = 6.7 Hz, 3H) 438B M +H = 540.10 (400 MHz, DMSO-d₆) δ 8.06-8.00 (m, 1H), 7.86-7.82 (m, 1H),7.79-7.72 (m, 3H), 7.53-7.47 (m, 2H), 5.11 (s, 2H), 4.51 (s, 2H),3.93-3.82 (m, 1H), 3.13-3.05 (m, 2H), 3.03-2.93 (m, 2H), 2.09-2.01 (m,1H), 1.05-0.98 (m, 2H), 0.83-0.78 (m, 2H) 456B M + H = 550.1 (400 MHz,Methanol-d₄) δ 7.78-7.74 (m, 1H), 7.73-7.65 (m, 4H), 7.57-7.51 (m, 2H),6.95 (t, J = 52.3 Hz, 1H), 5.20 (s, 2H), 4.54 (s, 2H), 3.99-3.89 (m,1H), 3.39-3.30 (m, 2H), 3.23-3.14 (m, 2H) 880B M + H = 482 (300 MHz,DMSO-d6) δ 8.53 (d, J = 2.5 Hz, 1H), 8.06-7.90 (m, 2H), 7.32 (dd, J =8.4, 5.6 Hz, 2H), 7.18 (t, J = 8.7 Hz, 2H), 4.96 (s, 2H), 4.71 (s, 2H),3.65 (t, J = 7.9 Hz, 1H), 3.12 (dd, J = 13.4, 6.9 Hz, 2H), 2.92 (t, J =11.7 Hz, 2H), 2.15 (tt, J = 8.5, 4.8 Hz, 1H), 1.12-1.01 (m, 2H),0.97-0.88 (m, 2H) 880A M + H = 482 (300 MHz, DMSO-d6) δ 8.56 (d, J = 2.4Hz, 1H), 8.14-7.99 (m, 2H), 7.31 (dd, J = 8.5, 5.5 Hz, 2H), 7.16 (t, J =8.8 Hz, 2H), 4.84 (s, 2H), 4.72 (s, 2H), 3.45 (q, J = 9.2 Hz, 1H), 3.03(t, J = 10.7 Hz, 2H), 2.78 (t, J = 10.9 Hz, 2H), 2.15 (tt, J = 8.8, 4.9Hz, 1H), 1.17-1.04 (m, 2H), 0.98-0.87 (m, 2H) 881B M + H = 442 (300 MHz,DMSO-d6) δ 9.11 (s, 1H), 8.53 (d, J = 2.5 Hz, 1H), 8.05-7.89 (m, 2H),7.39-7.28 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 4.98 (s, 2H), 4.72 (s, 2H),3.76 (t, J = 9.4 Hz, 1H), 3.15 (dd, J = 13.5, 6.8 Hz, 2H), 3.05-2.91 (m,2H). 881A M + H = 442 (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.56 (d, J =2.5 Hz, 1H), 8.15-8.00 (m, 2H), 7.30 (dd, J = 8.6, 5.6 Hz, 2H), 7.15 (t,J = 8.7 Hz, 2H), 4.86 (s, 2H), 4.73 (s, 2H), 3.65-3.48 (m, 1H), 3.07 (t,J = 10.5 Hz, 2H), 2.83 (t, J = 10.7 Hz, 2H).

Example 37: Synthesis of Compound 442B 1. Synthesis of Intermediate37-1B

To a solution of Intermediate 33-5B (200 mg, 0.42 mmol, 1.0 equiv) inDCM (2 mL) at 0° C. were added HATU (192 mg, 0.51 mmol, 1.2 equiv),1,1-dimethoxypropan-2-amine (55 mg, 0.46 mmol, 1.1 equiv), and DIEA (106mg, 1.1 mmol, 5.0 equiv). The mixture was stirred at 0° C. for 30 min,concentrated under reduced pressure, and purified by silica gelchromatography (12 g, 60 um, 0-10% MeOH in DCM gradient) to provideintermediate 37-1B. LRMS (ES) m/z 577.2 (M+H).

2. Synthesis of Intermediate 37-2B

To a solution of Intermediate 37-1B in DCM (3 mL) was added TFA (0.3mL). The mixture was stirred at r.t. for 15 h, concentrated underreduced pressure, and purified by silica gel chromatography (4 g, 60 um,0-10% MeOH in DCM gradient) to provide Intermediate 37-2B. LRMS (ES) m/z531.2 (M+H). As used in this example, the dashed bond --- indicates thatthe stereochemical configuration of the starting material is retained inthe product compound.

3. Synthesis of Compound 442B

To a solution of Intermediate 37-2B in DCE (2 mL) was added POCl₃ (1 mL)and the mixture was stirred at 100 0° C. for 1 h. The mixture wasconcentrated, diluted with DCM, and poured into NaOH (1 N) solution. Theaqueous layer was extracted with DCM (3×). The combined DCM layers werewashed with brine, dried over MgSO₄, filtered, concentrated, andpurified with reverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm,10-100% acetonitrile in water both with 0.1% formic acid gradient over40 min) to provide 33.9 mg (33% over 3 steps) of Compound 442B. LRMS(ES) m/z 513.1 (M+H). ¹H-NMR: (Methanol-d₄, 400 MHz, ppm) δ 7.79-7.74(m, 1H), 7.73-7.66 (m, 4H), 7.56-7.51 (m, 2H), 7.49 (q, J=1.3 Hz, 1H),5.20 (s, 2H), 4.53 (s, 2H), 3.75-3.65 (m, 1H), 3.35-3.25 (m, 2H),3.03-2.95 (m, 2H), 2.10 (d, J=1.3 Hz, 3H).

Example 38: Synthesis of Compound 475B

To a mixture of Intermediate 33-5B (50 mg, 0.10 mmol, 1.0 equiv) in THF(5 mL) was added borane in THF (1.0 M, 0.21 mL, 0.21 mmol, 2.0 equiv).The mixture was stirred at r.t. for 3 h, quenched with MeOH, andconcentrated under reduce pressure. This material was dissolved in 2 mLof DMF and purified with reverse phase HPLC (Phenomenex, gemini 5u C18150×21.2 mm, 10-70% acetonitrile in water both with 0.1% formic acidgradient over 25 min) to give a mixture, which was purified again withthe same conditions to give 4.3 mg (9%) of Compound 475B. LRMS (ES) m/z462.1 (M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 7.79-7.74 (m, 1H),7.72-7.65 (m, 4H), 7.52-7.47 (m, 2H), 5.12 (s, 2H), 4.48 (s, 2H),3.57-3.54 (m, 2H), 2.72-2.63 (m, 2H), 2.63-2.44 (m, 3H).

Example 39: Synthesis of Compound 479B 1. Synthesis of Intermediate 39-1

To solution of ethyl 3-oxocyclobutanecarboxylate (5.0 g, 35 mmol, 1.0equiv) in a mixture of dry dichloromethane (50 mL) and dry methanol (50mL) were added trimethylorthoformate (38 mL, 350 mmol, 10 equiv) andp-toluenesulfonic acid monohydrate (0.67 g, 3.5 mmol, 0.10 equiv)sequentially. The mixture was stirred overnight, concentrated, dilutedwith ethyl acetate, washed saturated sodium bicarbonate twice and brine,dried over magnesium sulfate, filtered, concentrated, and purified bysilica gel chromatography (80 g, 0-20% ethyl acetate in hexanes gradientover 25 minute) to give 4.6 g (70%) of ethyl3,3-dimethoxycyclobutane-1-carboxylate as a colorless oil (Intermediate39-1). ¹H NMR (400 MHz, Methylene Chloride-d₂) δ 4.26-4.11 (m, 2H), 3.17(s, 3H), 3.15 (s, 3H), 2.91-2.81 (m, 1H), 2.49-2.30 (m, 4H), 1.33-1.25(m, 3H).

2. Synthesis of Intermediate 39-2

To a solution of ethyl 3,3-dimethoxycyclobutane-1-carboxylate (1.0 g,5.3 mmol, 1.0 equiv) in dry THF (100 mL) at 0° C. was added methylmagnesium bromide in diethyl ether (3.0 M, 18 mL, 53 mmol, 10 equiv)dropwise. The mixture was heated at 85° C. for 2 h, cooled to 0° C.,quenched with HCl (4 M), stirred for 1 hour, and extracted with ethylacetate three times. The combined organic layers were dried overmagnesium sulfate, filtered, concentrated, and purified by silica gelchromatography (12 g, 0-100% ethyl acetate in hexanes gradient over 11minute) to give 0.78 g (quantitative) of3-(2-hydroxypropan-2-yl)cyclobutan-1-one (Intermediate 39-2) as a clearyellow oil. ¹H NMR (400 MHz, Methylene Chloride-d₂) δ 3.13-3.02 (m, 2H),2.99-2.88 (m, 2H), 2.50-2.40 (m, 1H), 1.28 (s, 6H).

3. Synthesis of Intermediate 39-3

To a mixture of 3-(2-hydroxypropan-2-yl)cyclobutan-1-one (0.78 g, 6.0mmol, 1.0 equiv) and 4-(dimethylamino)pyridine (37 mg, 0.30 mmol, 0.05equiv) in dry tetrahydrofuran (30 mL), cooled to 0° C., were addedtriethylamine (1.6 mL, 12 mmol, 1.9 equiv) and followed bychlorotrimethylsilane (1.2 mL, 9.1 mmol, 1.5 equiv) dropwise. Themixture was warmed to room temperature, stirred for 3 days, diluted withwater, and extracted with ethyl acetate twice. The combined organiclayers were washed with brine, dried over magnesium sulfate, filtered,concentrated, and purified by silica gel chromatography (12 g, 0-20%ethyl acetate in hexanes gradient over 11 minute) to give 1.1 g (92%) of3-(2-((trimethylsilyloxy)propan-2-yl)cyclobutan-1-one (Intermediate39-3) as a colorless oil. ¹H NMR (400 MHz, Methylene Chloride-d₂) δ3.07-2.98 (m, 2H), 2.86-2.76 (m, 2H), 2.32-2.23 (m, 1H), 1.25 (s, 6H),0.12 (s, 9H).

4. Synthesis of Intermediate 39-4

To a solution of 3-(2-((trimethylsilyl)oxy)propan-2-yl)cyclobutan-1-one(0.5 g, 2.5 mmol, 1.0 equiv) in dry methanol (7.5 mL) was added4-(trifluoromethyl)benzyl amine (0.36 g, 2.5 mmol, 1.0 equiv). Themixture was stirred for 5 min. To this mixture were added diphenylmethylisocyanide (0.48 g, 2.5 mmol, 1.0 equiv) and chloroacetic acid (0.24 g,2.5 mmol, 1.0 equiv). The mixture was stirred for 1 h, concentrated, andpurified by silica gel chromatography (40 g, 0-20% ethyl acetate inhexanes gradient over 14 minute) to give 0.86 g (53%) ofN-benzhydryl-1-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-3-(2-((trimethylsilyl)oxy)propan-2-yl)cyclobutane-1-carboxamide(Intermediate 39-4, mixture of stereoisomers) as a white solid. LRMS(ES) 573 (M+H-TMS). ¹H NMR (400 MHz, Methylene Chloride-d₂) δ 7.68-7.23(m, 14H), 6.14-6.06 (m, 1H), 4.67-4.52 (m, 2H), 3.94-3.80 (m, 2H),2.69-2.59 (m, 2H), 2.26-2.16 (m, 2H), 1.94-1.82 (m, 1H), 1.10-1.02 (m,6H), 0.44-−0.00 (m, 9H).

5. Synthesis of Diastereomer 39-5B

To a solution ofN-benzhydryl-1-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-3-(2-((trimethylsilyl)oxy)propan-2-yl)cyclobutane-1-carboxamide(0.86 g, 1.3 mmol, 1.0 equiv) in dry THF (9 mL) at 0° C. was added LHMDS(1.0 M, 1.6 mL, 1.6 mmol, 1.2 equiv) in dry THF (9 mL) dropwise. Themixture was stirred at 0° C. for 2 h, slowly quenched with MeOH,concentrated, and purified by silica gel chromatography (40 g, 0-20%ethyl acetate in hexanes gradient over 28 minute) to give Diastereomer39-5A which was discarded and 0.4 g (49%) of Diastereomer 39-5B as acolorless oil. LRMS (ES) 537 (M+H-TMS). ¹H NMR (400 MHz, MethyleneChloride-d₂) δ 7.60-7.56 (m, 2H), 7.42-7.34 (m, 6H), 7.30-7.25 (m, 2H),7.21-7.17 (m, 4H), 6.99 (s, 1H), 4.97 (s, 2H), 3.71 (s, 2H), 2.98-2.88(m, 2H), 2.17-2.04 (m, 3H), 1.06 (s, 6H), 0.12 (s, 9H).

6. Synthesis of Intermediate 39-6B

To a solution of Diastereomer 39-5B (0.40 g, 0.65 mmol, 1.0 equiv) inethyl acetate (25 mL) was added 20% palladium hydroxide on carbon (1.5g, 2.1 mmol, 3.3 equiv), and the resulting mixture is sparged withhydrogen for 5 min, followed by stirring under 500 psi in a Parrpressure reactor at 50° C. for 18 h. The reaction mixture was thencooled, filtered through a pad of celite, concentrated, and purified bychromatography (12 g, 60 um, 0-10% methanol in dichloromethane gradientover 22 minute) to give 0.13 g (57%) of intermediate 39-6B as a whitesolid. LRMS (ES) 371 (M+H). ¹H NMR (400 MHz, Methylene Chloride-d₂) δ7.64-7.56 (m, 2H), 7.38-7.30 (m, 2H), 6.80-6.55 (m, 1H), 5.01-4.93 (m,2H), 4.05-4.02 (m, 2H), 2.98-2.85 (m, 2H), 2.48-2.24 (m, 3H), 1.06-1.02(m, 6H). As used in this example, the dashed bond --- indicates that thestereochemical configuration of the starting material is retained in theproduct compound.

7. Synthesis of Compound 479B

4-Bromo-3-fluorobenzonitrile (65 mg, 0.33 mmol, 1.8 equiv), copper (I)iodide (17 mg, 0.090 mmol, 0.50 equiv), and potassium carbonate (75 mg,0.54 mmol, 3.0 equiv) were combined in a flask which was vacuum-nitrogenpurged 3 times. To this mixture were added N,N-dimethylethylenediamine(0.010 mL, 0.090 mmol, 0.50 equiv), intermediate 6-6B (67 mg, 0.18 mmol,1.0 equiv), and dry dioxane (1 mL). The reaction vessel was then heatedat 100° C. with stirring overnight, cooled to r.t., filtered, andpurified by reverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm,10-90% acetonitrile in water with 0.1% formic acid in 25 minutes Thecombined fractions was purified again by silica gel chromatography (4 g,60 um, 0-100% ethyl acetate in hexanes gradient over 11 min) to give 34mg (38%) of Compound 479B. LRMS (ES) 490 (M+H). ¹H NMR (400 MHz,Methanol-d₄) δ 7.78-7.73 (m, 1H), 7.70-7.63 (m, 4H), 7.49-7.44 (m, 2H),5.14 (s, 2H), 4.48 (s, 2H), 3.00-2.87 (m, 2H), 2.47-2.32 (m, 3H), 1.05(s, 6H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 479B:

Diastereomer No. LRMS (ES) m/z ¹H NMR 479B M + H = 490.2 (400 MHz,Methanol-d₄) δ 7.78-7.73 (m, 1H), 7.70-7.63 (m, 4H), 7.49-7.44 (m, 2H),5.14 (s, 2H), 4.48 (s, 2H), 3.00-2.87 (m, 2H), 2.47-2.32 (m, 3H), 1.05(s, 6H) 481B M + H = 499.1 (400 MHz, Methanol-d₄) δ 7.70-7.66 (m, 2H),7.51-7.44 (m, 3H), 7.43-7.40 (m, 1H), 7.35-7.32 (m, 1H), 5.15 (s, 2H),4.44 (s, 2H), 3.02-2.91 (m, 2H), 2.49-2.33 (m, 3H), 1.07 (s, 6H)

Example 40: Synthesis of Compound 436B 1. Synthesis of Intermediate 40-2

To a solution of tert-butyl 3-oxocyclobutanecarboxylate (5.8 g, 34 mmol,1.0 equiv) in dry methanol (75 mL) at 0° C. was added4-(trifluoromethyl)benzyl amine (4.8 mL, 34 mmol, 1.0 equiv). Themixture was immediately warmed to r.t., stirred for 5 min at r.t., andcooled back down to 0° C., followed by addition of4-methoxybenzylisocyanide (5.0 g, 34 mmol, 1.0 equiv) and chloroaceticacid (3.2 g, 34 mmol, 1.0 equiv) sequentially, warmed to r.t., stirredfor 1 h, concentrated, and purified by silica chromatography using EA/HE(gradient from 0-100% and 100%) and then MeOH/DCM (1/9) as eluents togive 11.4 g (79%) of3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-3-((4-methoxybenzyl)carbamoyl)cyclobutane-1-carboxylateas a mixture of isomers. LRMS (ES) m/z 569 (M+H). ¹H NMR (400 MHz,Methylene Chloride-d₂) δ 7.71-7.61 (m, 2H), 7.46-7.37 (m, 2H), 7.28-7.19(m, 2H), 6.93-6.87 (m, 2H), 4.69-4.62 (m, 2H), 4.42-4.36 (m, 2H),3.93-3.88 (m, 2H), 3.84-3.81 (m, 3H), 3.03-2.75 (m, 3H), 2.73-2.61 (m,1H), 2.55-2.45 (m, 1H), 1.43 (s, 9H).

2. Synthesis of Intermediate 40-3B

To a solution of3-(2-Chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-3-((4-methoxybenzyl)carbamoyl)cyclobutane-1-carboxylate(11.4 g, 20 mmol, 1.0 equiv) in THF (60 mL) cooled to 0° C. was addedsodium hydroxide (1 N, 60.0 mL, 60.1 mmol, 3.0 equiv) in water dropwise.The mixture was allowed to warm to r.t., stirred for 3 h, concentratedpartially, and extracted with ethyl acetate three times. The combinedorganic washes were dried over magnesium sulfate, filtered,concentrated, and purified by silica chromatography using EA/HE(gradient from 0-50%, isocratic at 50%, gradient from 50-100%) to givethe first eluted diastereomer 40-3A which was discarded and 2.1 g (20%)of the second eluted diastereomer 40-3B. LRMS (ES) m/z 533 (M+H). ¹H NMR(400 MHz, Methylene Chloride-d₂) δ 7.66-7.61 (m, 2H), 7.36-7.31 (m, 2H),7.28-7.23 (m, 2H), 6.96-6.90 (m, 2H), 4.93 (s, 2H), 4.61 (s, 2H), 3.89(s, 2H), 3.83 (s, 3H), 3.11-3.04 (m, 2H), 3.02-2.93 (m, 1H), 2.58-2.51(m, 2H), 1.48 (s, 9H). As used in this example, the dashed bond ---indicates that the stereochemical configuration of the starting materialis retained in the product compound.

3. Synthesis of Intermediate 40-4B

To a solution of 40-3B (2.1 g, 3.9 mmol, 1.0 equiv) in acetonitrile (32mL) cooled at 0° C. was added cerium (IV) ammonium nitrate (6.4 g, 11.7mmol, 3.0 equiv) in water (16 mL) dropwise. The mixture was sonicatedfor 10 min, stirred for 1 h at r.t., concentrated, and extracted withethyl acetate three times. The combined organic washes were dried overmagnesium sulfate, filtered, concentrated, and purified by silicachromatography using MeOH/DCM (gradient from 0-10%) as eluents. Thefractions were collected and purified again by silica gel chromatographyusing EA/HE (gradient from 0-100%) as eluent to give 0.44 g (28%) of40-4B. LRMS (ES) m/z 357 (M+H-tertbutyl). ¹H NMR (400 MHz, MethyleneChloride-d₂) δ 7.68-7.60 (m, 2H), 7.42-7.34 (m, 2H), 4.96 (s, 2H),4.07-4.04 (m, 2H), 3.09-2.92 (m, 3H), 2.62-2.54 (m, 2H), 1.46 (s, 9H).

4. Synthesis of Intermediate 40-5B

To a mixture of 40-4B (0.37 g, 0.90 mmol, 1.0 equiv),4-bromo-3-fluorobenzonitrile (0.33 g, 1.6 mmol, 1.8 equiv), copper (I)iodide (0.086 g, 0.45 mmol, 0.5 equiv), and potassium carbonate (0.38 g,2.7 mmol, 3.0 equiv) in a vacuum-nitrogen purged flask were addedN,N-dimethylethylenediamine (0.049 mL, 0.45 mmol, 0.5 equiv) and drydioxane (4 mL). The mixture was heated at 100° C. for 15 h, filteredthrough celite, concentrated, and purified by silica chromatographyusing EA/HE (gradient from 0-100%) as eluent to give 0.29 g (61%) of40-5B. LRMS (APCI) m/z 476.1 (M+H-C₄H₉ ¹H NMR (400 MHz, MethyleneChloride-d₂) δ 7.70-7.66 (m, 2H), 7.63-7.60 (m, 1H), 7.60-7.56 (m, 1H),7.56-7.51 (m, 1H), 7.44-7.40 (m, 2H), 5.02 (s, 2H), 4.40-4.38 (m, 2H),3.18-3.11 (m, 2H), 3.03-2.94 (m, 1H), 2.70-2.62 (m, 2H), 1.42 (s, 9H).

5. Synthesis of Intermediate 40-6B

40-5B (0.29 g, 0.55 mmol, 1.0 equiv) and TFA (3.0 mL, 39 mmol, 71 equiv)were combined, stirred for 30 min, concentrated, and dried under vacuumto give 40-6B. LRMS (ES) m/z 476 (M+H).

6. Synthesis of Intermediate 40-7B

To a mixture of 1-aminopropan-2-one HCl (10 mg, 0.092 mmol, 0.92 equiv),PyBop (52 mg, 0.10 mmol, 1.0 equiv), and 40-6B (49 mg, 0.10 mmol, 1.0equiv) in dry DCM (1 mL) was added DIEA (0.073 mL, 0.42 mmol, 4.2equiv). The mixture was stirred for 30 min at r.t., concentrated, andpurified by silica chromatography using MeOH/DCM (gradient from 0-10%)to give 45 mg (92%) of 40-7B. LRMS (ES) m/z 531 (M+H).

7. Synthesis of Compound 436B

To a solution of 40-7B (45 mg, 0.085 mmol, 1.0 equiv) in DCE (1 mL) wasadded phosphorus (V) oxychloride (0.39 mL, 4.2 mmol, 50 equiv) dropwise.The mixture was heated at 100° C. for 1 h, cooled to 0° C., basified topH greater than 14 with NaOH (1 N) dropwise, warmed to r.t., and stirredovernight. The mixture was extracted with DCM three times. The combinedorganic layers were dried over magnesium sulfate, filtered,concentrated, and purified by RP-HPLC (Phenomenex, gemini 5u C18150×21.2 mm, 10-100% acetonitrile in water both with 0.1% formic acidgradient over 25 min) to give 14.9 mg (35%) of Compound 436B. LRMS (ES)m/z 513 (M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 7.80-7.75 (m, 1H),7.73-7.66 (m, 4H), 7.56-7.51 (m, 2H), 6.66 (q, J=1.2 Hz, 1H), 5.20 (s,2H), 4.54 (s, 2H), 3.74-3.63 (m, 1H), 3.31-3.24 (m, 2H), 3.02-2.94 (m,2H), 2.27 (d, J=1.2 Hz, 3H).

Example 41: Synthesis of Compound 496 1. Synthesis of Intermediate 41-2

To a mixture of (4-(trifluoromethyl)phenyl)methanamine (143 mg, 0.82mmol, 1.05 equiv) and 3-(5-methylthiazol-2-yl)cyclobutan-1-one (130 mg,0.78 mmol, 1.0 equiv) in MeOH (10 mL) were added 2-isocyanopropane (56mg, 0.82 mmol, 1.05 equiv) and chloroacetic acid (77 mg, 0.82 mmol, 1.05equiv). The mixture was stirred at r.t. for 1 h, concentrated underreduced pressure, and purified by silica gel chromatography usingEtOAc/Hexanes (7/3) as eluents to provide 380 mg of Intermediate 41-2 asa mixture of isomers which were used in the subsequent step withoutfurther purification LRMS (ES) m/z 488.1 (M+H).

2. Synthesis of Compound 496B

To a mixture of Intermediate 41-2 (380 mg, 0.78 mmol, 1.0 equiv.) in THF(5 mL) cooled to 0° C. with an ice bath was added LHMDS (1 M in THF,0.78 mL, 0.78 mmol, 1.0 equiv) dropwise. The mixture was stirred at 0°C. for 2 h, added MeOH, concentrated under reduced pressure, andpurified with reverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm,10-80% acetonitrile in water both with 0.1% formic acid gradient over 40min) to provide 3.6 mg (2% over 2 steps) of the first eluted eluent peakas Diastereomer 496B and 8.1 mg (5% over 2 steps) of the second elutedpeak as Diastereomer 496A.

Characterization for Diastereomer 496B: LRMS (ES) m/z 452.1 (M+H). NMR(Methanol-d₄, 400 MHz, ppm) δ 7.68 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.0 Hz,2H), 7.31 (q, J=1.2 Hz, 1H), 5.14 (s, 2H), 4.70 (p, J=6.8 Hz, 1H), 4.06(s, 2H), 3.93-3.77 (m, 1H), 3.20-3.08 (m, 2H), 2.98-2.86 (m, 2H), 2.45(d, J=1.2 Hz, 3H), 1.22 (d, J=6.8 Hz, 6H).

Characterization for Diastereomer 496A: LRMS (ES) m/z 452.1 (M+H). ¹HNMR (400 MHz, Methanol-d₄) δ 7.65 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.0 Hz,2H), 7.36 (q, J=1.2 Hz, 1H), 5.07 (s, 2H), 4.86-4.74 (m, 1H), 4.08 (s,2H), 3.69 (p, J=8.9 Hz, 1H), 2.99 (ddd, J=10.0, 8.4, 2.7 Hz, 2H), 2.76(td, J=9.5, 2.8 Hz, 2H), 2.43 (d, J=1.2 Hz, 3H), 1.26 (d, J=6.8 Hz, 6H).

Example 42: Synthesis of Compound 498B 1. Synthesis of Intermediate 42-1

To a mixture of (4-(trifluoromethyl)phenyl)methanamine (6.7 g, 38.0mmol, 1.05 equiv) and tert-butyl 3-oxocyclobutane-1-carboxylate (6.2 g,36.2 mmol, 1.0 equiv) in MeOH (100 mL) were added 2-isocyanopropane (3.0g, 43.4 mmol, 1.2 equiv) and chloroacetic acid (3.6 mg, 38.0 mmol, 1.05equiv). The mixture was stirred at r.t. for 1 h, concentrated underreduced pressure, and purified with silica gel chromatography usingEtOAc/Hexanes (7/3) as eluents to provide intermediate 42-1 as a mixtureof diastereomers which was used in the subsequent step without furtherpurification. LRMS (ES) m/z 491.2 (M+H)

2. Synthesis of Diastereomer 42-2B

To a solution of intermediate 42-1 (16.5 g, 33.6 mmol, 1.0 equiv.) inTHF (200 mL) cooled to 0° C. with an ice bath was added LHMDS (1 M inTHF, 40.3 mL, 40.3 mmol, 1.2 equiv) dropwise. The mixture was stirred at0° C. for 2 h, added MeOH, concentrated under reduced pressure, andpurified with silica gel chromatography (220 g, 0-50% EtOAc in hexanesgradient) to provide impure product. This material was purified again bysilica gel chromatography (120 g, 0-50% EtOAc in hexanes gradient) toprovide the first eluting Diastereomer 42-2A which was discarded and 2.5g (16%) of the second eluting Diastereomer 42-2B.

Characterization for Diastereomer 42-2B: LRMS (ES) m/z 455.25 (M+H). ¹HNMR (400 MHz, Methanol-d₄) δ 7.72-7.63 (m, 2H), 7.45-7.36 (m, 2H), 5.03(s, 2H), 4.72 (p, J=6.9 Hz, 1H), 4.02 (s, 2H), 3.11-2.89 (m, 3H),2.71-2.56 (m, 2H), 1.46 (s, 9H), 1.23 (d, J=6.8 Hz, 6H).

3. Synthesis of Intermediate 42-3B

To a solution of Diastereomer 42-2B (2.5 g, 5.5 mmol, 1.0 equiv.) in DCM(10 mL) was added TFA (10 mL). The mixture was stirred at r.t. for 1 hand concentrated to give 2.2 g (99% yield) of intermediate 42-3B. LRMS(ES) m/z 399.2 (M+H).

4. Synthesis of Compound 498B

To a solution of 42-3B (0.20 g, 0.50 mmol, 1.0 equiv) in DCM (3 mL) wereadded thionyl chloride (0.2 mL, 2.7 mmol, 5.5 equiv) and a drop of DMF(˜50 mg). The mixture was stirred at r.t. for 1 min, followed byaddition of MeNH₂ (2 M in THF, 6 mL, 12 mmol, 24 equiv), stirred at r.t.for 1 h, poured into water, and extracted with DCM. The organic layerwas concentrated and purified by reverse phase HPLC (Phenomenex, gemini5u C18 150×21.2 mm, 10-700% acetonitrile in water both with 0.1% formicacid gradient over 25 min) to give 8.6 mg (4%) of Compound 498B. LRMS(ES) m/z 412.2 (M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 7.81-7.72 (m, 1H),7.67-7.62 (m, 2H), 7.42-7.36 (m, 2H), 5.04 (s, 2H), 4.70 (hept, J=6.8Hz, 1H), 4.01 (s, 2H), 3.14-2.96 (m, 3H), 2.74-2.69 (m, 3H), 2.66-2.56(m, 2H), 1.20 (d, J=6.8 Hz, 6H).

Example 43: Synthesis of Compound 500B 1. Synthesis of Intermediate43-1B

To a mixture of 3-aminobutan-2-one (68 mg, 0.55 mmol, 1.1 equiv), HATU(229 mg, 0.60 mmol, 1.2 equiv), and 42-3B (200 mg, 0.50 mmol, 1.0 equiv)in dry DCM (2 mL) was added DIEA (0.35 mL, 2.0 mmol, 4.0 equiv). Themixture was stirred for 1 h at r.t., concentrated, and purified bysilica chromatography using MeOH/DCM (gradient from 0-10%) to give 239mg of 43-1B. LRMS (ES) m/z 468.2 (M+H). As used in this example, thedashed bond --- indicates that the stereochemical configuration of thestarting material is retained in the product compound.

2. Synthesis of Compound 500B

To a solution of 43-1B (239 mg, 0.50 mmol, 1.0 equiv) in DCE (3 mL) wasadded phosphorus (V) oxychloride (2.4 mL, 25.5 mmol, 50 equiv) dropwise.The mixture was heated at 100° C. for 1 h, cooled to 0° C., basified topH greater than 14 with NaOH (1 N) dropwise, warmed to r.t., and stirredovernight. The mixture was extracted with DCM three times. The combinedorganic layers were dried over magnesium sulfate, filtered,concentrated, and purified by reverse phase HPLC (Phenomenex, gemini 5uC18 150×21.2 mm, 10-100% acetonitrile in water both with 0.1% formicacid gradient over 25 min) to give 103 mg (45%) of compound 500B. LRMS(ES) m/z 450.2 (M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 7.70-7.65 (m, 2H),7.47-7.42 (m, 2H), 5.11 (s, 2H), 4.68 (hept, J=6.8 Hz, 1H), 4.05 (s,2H), 3.63-3.51 (m, 1H), 3.21-3.13 (m, 2H), 2.87-2.77 (m, 2H), 2.23-2.21(m, 3H), 2.04-2.02 (m, 3H), 1.22 (d, J=6.8 Hz, 6H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 500B:

Diastereomer LRMS (ES) No. m/z ¹H NMR 500B M + H = 450.2 (400 MHz,Methanol-d₄) δ 7.70-7.65 (m, 2H), 7.47-7.42 (m, 2H), 5.11 (s, 2H), 4.68(hept, J = 6.8 Hz, 1H), 4.05 (s, 2H), 3.63-3.51 (m, 1H), 3.21-3.13 (m,2H), 2.87-2.77 (m, 2H), 2.23-2.21 (m, 3H), 2.04-2.02 (m, 3H), 1.22 (d, J= 6.8 Hz, 6H) 502B M + H = 436.2 (400 MHz, Methanol-d₄) δ 7.70-7.65 (m,2H), 7.51 (q, J = 1.3 Hz, 1H), 7.47-7.42 (m, 2H), 5.12 (s, 2H), 4.67(hept, J = 6.8 Hz, 1H), 4.05 (s, 2H), 3.68-3.58 (m, 1H), 3.23-3.16 (m,2H), 2.90-2.81 (m, 2H), 2.12 (d, J = 1.3 Hz, 3H), 1.22 (d, J = 6.8 Hz,6H)

Example 44: Synthesis of Compounds 488B and 490B 1. Synthesis ofIntermediate 44-2

To a mixture of 4-chlorobenzyl amine (2.9 g, 20.2 mmol, 1.0 equiv) andtert-butyl 3-oxocyclobutane-1-carboxylate (3.4 g, 20.2 mmol, 1.0 equiv)in MeOH (30 mL) were added (isocyanomethylene)dibenzene (4.1 g, 21.2mmol, 1.05 equiv) and chloroacetic acid (2.0 g, 21.2 mmol, 1.05 equiv).The mixture was stirred at r.t. for 15 h, concentrated under reducedpressure, and purified by silica gel chromatography using EA/HE(gradient from 0-100%) to provide 9.0 g (77%) of tert-butyl3-(benzhydrylcarbamoyl)-3-(2-chloro-N-(4-chlorobenzyl)acetamido)cyclobutane-1-carboxylate) as a mixture of diastereomers. LRMS (ES) m/z581.2 (M+H).

2. Synthesis of Diastereomer 44-2B

To a solution of tert-butyl3-(benzhydrylcarbamoyl)-3-(2-chloro-N-4-(chlorobenzyl)acetamido)cyclobutane-1-carboxylate)(9.0 g, 15.5 mmol, 1.0 equiv) in THF (200 mL) cooled to 0° C. with anice bath was added LHMDS (1 M in THF, 18.6 mmol, 1.2 equiv) dropwiseover 10 minutes. The mixture was stirred at 0° C. for 2 h, quenched withMeOH (5 mL), concentrated onto SiO₂ (20 g), and purified by silica gelchromatography using EA/HE (gradient from 0-100%) to provide twoseparate diastereomers. The first eluted peak (Diastereomer 44-2A) wasdiscarded and the second eluted peak (Diastereomer 44-2B) was collected(3.0 g, 36%). Characterization of Diastereomer 44-2B: LRMS (ES) m/z545.3 (M+H). ¹H-NMR (Methanol-d₄, 400 MHz, ppm) δ 7.45-7.30 (m, 8H),7.24-7.12 (m, 6H), 6.99 (s, 1H), 4.88 (s, 2H), 3.77 (s, 2H), 3.08-2.86(m, 3H), 2.69-2.51 (m, 2H), 1.44 (s, 9H).

3. Synthesis of Intermediate 44-4B

To a solution of diastereomer 44-2B (0.6 g, 1.1 mmol, 1.0 equiv) in TFA(20 mL) was added Et₃SiH (20 mL). The mixture was stirred at 80° C. for60 h, concentrated under reduced pressure, and purified by silica gelchromatography using MeOH/DCM (0-30%) to provide 0.3 g (84%) ofIntermediate 44-4B. LRMS (ES) m/z 323.1 (M+H). As used in this example,the dashed bond --- indicates that the stereochemical configuration ofthe starting material is retained in the product compound.

4. Synthesis of Intermediate 44-5B

To a solution of Intermediate 44-4B (354 mg, 1.1 mmol) in a mixture ofDCM (5 mL) and MeOH (5 mL) was added TMSCHN₂ (2 M in hexanes, 2.8 mL,5.1 equiv). The mixture was stirred at r.t. for 2 h and concentratedunder reduced pressure to provide Intermediate 44-5B. LRMS (ES) m/z337.1 (M+H).

5. Synthesis of Compound 488B

To a mixture of copper iodide (113 mg, 0.59 mmol, 0.5 equiv), potassiumcarbonate (492 mg, 3.6 mmol, 3.0 equiv), 4-bromo-3-fluorobenzonitrile(428 mg, 2.1 mmol, 1.8 equiv), and intermediate 44-5B (370 mg, 1.1 mmol,1.0 equiv.) in a vial were added 1,4-dioxane (16 mL) andN,N′-dimethylethylene diamine (64 μL, 0.59 mmol, 0.5 equiv). The mixturewas sealed and heated at 100° C. for 15 h, cooled to r.t., filteredthrough celite, and purified by silica gel chromatography using EA/HE(gradient from 0-100%) to provide 100 mg (19% over 3 steps) of Compound488B. LRMS (ES) m/z 456.1 (M+H). ¹H-NMR: (400 MHz, Methanol-d₄) δ7.78-7.73 (m, 1H), 7.71-7.63 (m, 2H), 7.40-7.35 (m, 2H), 7.31-7.26 (m,2H), 4.99 (s, 2H), 4.47 (s, 2H), 3.64 (s, 3H), 3.18-3.02 (m, 3H),2.87-2.78 (m, 2H).

6. Synthesis of Compound 490B

To a solution of Compound 488B (70 mg, 0.15 mmol, 1.0 equiv) in MeOH (2mL) was added NH₄OH (2 mL). The resulting mixture was stirred at r.t.for 5 h, concentrated in vacuo, and purified by reverse phase HPLC(Phenomenex, gemini 5u C18 150×21.2 mm, 10-100% acetonitrile in waterboth with 0.1% formic acid gradient over 40 min) to provide 2.4 mg (4%)of Isomer B of Compound 490 (490B). LRMS (ES) m/z 441.1 (M+H). ¹H-NMR:(Methanol-d₄, 400 MHz, ppm) δ 7.80-7.75 (m, 1H), 7.73-7.65 (m, 2H),7.43-7.36 (m, 2H), 7.34-7.28 (m, 2H), 5.04 (s, 2H), 4.49 (s, 2H),3.21-3.06 (m, 3H), 2.84-2.68 (m, 2H).

Example 45: Synthesis of Compounds 492B 1. Synthesis of Intermediate45-1B

To a mixture of piperidin-4-ol (269 mg, 2.7 mmol, 1.1 equiv), HATU (1.1g, 2.9 mmol, 1.2 equiv), and 44-4B (0.78 g, 2.4 mmol, 1.0 equiv) in dryDCM (10 mL) was added TEA (1.0 mL, 7.3 mmol, 3.0 equiv). The mixture wasstirred for 3 h at r.t., concentrated, and purified by silicachromatography using MeOH/DCM (gradient from 0-30%) to give 150 mg (15%)of 45-1B. LRMS (ES) m/z 406.2 (M+H).

2. Synthesis of Compound 492B

To a mixture of copper iodide (12 mg, 0.062 mmol, 0.5 equiv), potassiumcarbonate (51 mg, 0.37 mmol, 3.0 equiv), 4-bromo-3-fluorobenzonitrile(44 mg, 0.22 mmol, 1.8 equiv), and intermediate 45-1B (50 mg, 0.12 mmol,1.0 equiv) in vial were added 1,4-dioxane (3 mL) andN,N′-dimethylethylene diamine (7 μL, 0.062 mmol, 0.5 equiv). The mixturewas sealed and heated at 100° C. for 15 h, cooled to r.t., filteredthrough celite, and purified by reverse phase HPLC (Phenomenex, gemini5u C18 150×21.2 mm, 10-80% acetonitrile in water both with 0.1% formicacid gradient over 40 min) to provide 13.1 mg (20%) of compound 492B.LRMS (ES) m/z 525.2 (M+H). ¹H-NMR: (400 MHz, Methanol-d₄) δ 7.79-7.75(m, 1H), 7.72-7.66 (m, 2H), 7.43-7.39 (m, 2H), 7.37-7.32 (m, 2H),5.10-5.00 (m, 2H), 4.55-4.45 (m, 2H), 4.04-3.95 (m, 1H), 3.86-3.78 (m,1H), 3.51-3.42 (m, 1H), 3.22-3.01 (m, 5H), 2.81-2.70 (m, 2H), 1.87-1.77(m, 2H), 1.45-1.34 (m, 2H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 492B:

Compound No. LRMS (ES) m/z ¹H NMR 492B M + H = 525.2 (400 MHz,Methanol-d₄) δ 7.79-7.75 (m, 1H), 7.72-7.66 (m, 2H), 7.43-7.39 (m, 2H),7.37-7.32 (m, 2H), 5.10-5.00 (m, 2H), 4.55-4.45 (m, 2H), 4.04-3.95 (m,1H), 3.86-3.78 (m, 1H), 3.51-3.42 (m, 1H), 3.22-3.01 (m, 5H), 2.81-2.70(m, 2H), 1.87-1.77 (m, 2H), 1.45-1.34 (m, 2H) 494B M + H = 534.1 (400MHz, Methanol-d₄) δ 7.48-7.43 (m, 1H), 7.42-7.36 (m, 3H), 7.35-7.29 (m,3H), 5.09-4.98 (m, 2H), 4.47-4.37 (m, 2H), 4.02-3.93 (m, 1H), 3.84-3.76(m, 1H), 3.49-3.40 (m, 1H), 3.20-2.99 (m, 5H), 2.78-2.68 (m, 2H),1.85-1.75 (m, 2H), 1.43-1.32 (m, 2H)

Example 46: Synthesis of Compound 483B 1. Synthesis of Diastereomers46-1A and 46-1B

To a mixture of 3-((tert-butyldimethylsilyl)oxy)cyclobutan-1-one (1.0 g,5.0 mmol) and (4-(trifluoromethyl)phenyl)methanamine (874 mg, 5.0 mmol)in a RB flask was added MeOH (10 mL). The mixture was stirred at r.t.for 5 min. To this mixture were added (isocyanomethylene)dibenzene (965mg, 5.0 mmol) and 2-chloroacetic acid (472 mg, 5.0 mmol) sequentially.The resulting mixture was stirred at r.t. for 5 h, diluted with EtOAc(150 mL), washed with saturated aqueous NaHCO₃ (50 mL), saturatedaqueous NH₄Cl (50 mL), and brine, dried over sodium sulfate,concentration under reduced pressure, and purified by silicachromatography using 20% EA/Hex to provide 1.2 g (1.8 mmol, 36% yield)of the first eluting Diastereomer 46-1A and 698 mg (1.08 mmol, 21%yield) of the second eluting Diastereomer 46-1B.

Characterization of Diastereomer 46-1A: LRMS (APCI) m/z 645.3 (M+H). ¹HNMR (400 MHz, Methanol-d₄) δ 7.57 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.1 Hz,2H), 7.41-7.10 (m, 10H), 6.13 (s, 1H), 4.82 (s, 2H), 4.24 (s, 2H), 4.18(t, J=7.0 Hz, 1H), 3.07 (ddd, J=9.8, 6.8, 3.0 Hz, 2H), 2.26 (t, J=9.9Hz, 2H), 0.84 (s, 9H), 0.00 (s, 6H).

Characterization of Diastereomer 46-1B: LRMS (APCI) m/z 645.3 (M+H). ¹HNMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz,2H), 7.37-7.25 (m, 10H), 6.18 (s, 1H), 4.75 (s, 2H), 4.28-4.22 (m, 1H),4.18 (s, 2H), 2.85-2.74 (m, 2H), 2.66-2.53 (m, 2H), 0.74 (s, 9H), −0.12(s, 6H).

2. Synthesis of Intermediate 46-2B

To a solution of Diastereomer 46-1B (698 mg, 1.08 mmol) in THF (5 mL)cooled to 0° C. with an ice bath was added LHMDS (1.3 mL, 1.3 mmol, 1.2equiv) was dropwise over 5 min. The mixture was stirred at 0° C. for 1h, quenched with saturated aqueous NH₄Cl (30 mL), and diluted with EtOAc(75 mL). The organic phase was washed with brine, dried over sodiumsulfate, concentrated under reduced pressure, and purified by silica gelchromatography using 10% EtOAc/Hex as eluent to provide 600 mg (92%) ofIntermediate 46-2B. LRMS (APCI) m/z 609.3 (M+H).

3. Synthesis of Intermediate 46-3B

To a solution of intermediate 46-2B (600 mg, 0.99 mmol) in a mixture ofMeOH (25 mL), EtOAc (25 mL) and Acetic acid (0.5 mL) was added Pd(OH)₂.The mixture was sparged with hydrogen for 5 min, stirred under 400 psihydrogen for 20 h, filtered through celite, concentrated in vacuo, anddissolved in EtOAc (75 mL). The organic phase was washed with saturatedaqueous NaHCO₃ (50 mL) and brine, dried over sodium sulfate,concentrated under reduced pressure, and purified by silica gelchromatography using 50% EtOAc/Hex and 5% MeOH/DCM as eluent to provide256 mg (79%) of Intermediate 46-3B. LRMS (APCI) m/z 329.1 (M+H). ¹H NMR(400 MHz, Methanol-d₄) δ 7.72 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H),5.03 (s, 2H), 4.35 (p, J=7.2 Hz, 1H), 4.10 (s, 2H), 2.79 (d, J=7.2 Hz,4H).

4. Synthesis of Compound 483B

To a mixture of intermediate 46-3B (100 mg, 0.31 mmol), K₂CO₃ (126 mg,0.91 mmol, 3.0 equiv), CuI (29 mg, 0.15 mmol, 0.5 equiv) and1-bromo-4-chloro-2-fluorobenzene (57 μL, 0.46 mmol, 1.5 equiv) wereadded anhydrous 1,4-dioxane (3 mL) and N,N-dimethylethylenediamine (16μL, 0.15 mmol, 0.5 equiv). The resulting suspension was heated in asealed tube under nitrogen at 115° C. for 18 h, cooled to roomtemperature, filtered through celite, washed with additional 1,4-dioxane(20 mL), evaporated in vacuo, and purified with reverse phase HPLC using10-100% ACN/water (both with 0.1% formic acid; Phenomenex Gemini 5micron C18 column) and silica gel chromatography using 75% EA/Hex aseluent to provide 19 mg (14%) of Compound 483B. LRMS (APCI) m/z 457.1(M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 7.69-7.64 (m, 2H), 7.49-7.39 (m,4H), 7.35-7.31 (m, 1H), 5.03 (s, 2H), 4.43 (s, 2H), 4.33-4.24 (m, 1H),2.86-2.76 (m, 4H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 483B:

The final compounds derived from diastereomer 46-1A were isolated usingDiastereomer 46-1A as the starting material in an analogous sequence.

Compound No. LRMS (ES) m/z ¹H NMR 483B M + H = 457.1 (400 MHz,Methanol-d₄) δ 7.69-7.64 (m, 2H), 7.49-7.39 (m, 4H), 7.35-7.31 (m, 1H),5.03 (s, 2H), 4.43 (s, 2H), 4.33-4.24 (m, 1H), 2.86-2.76 (m, 4H) 484BM + H = 448.1 (400 MHz, Methanol-d₄) δ 7.79-7.74 (m, 1H), 7.71-7.64 (m,4H), 7.49-7.43 (m, 2H), 5.03 (s, 2H), 4.49 (s, 2H), 4.33-4.23 (m, 1H),2.88-2.76 (m, 4H) 483A M + H = 457.1 (400 MHz, Methanol-d₄) δ 7.70-7.62(m, 2H), 7.51-7.37 (m, 4H), 7.36-7.29 (m, 1H), 5.07 (s, 2H), 4.44 (s,2H), 4.21-4.11 (m, 1H), 3.00-2.89 (m, 2H), 2.47-2.36 (m, 2H) 484A M + H= 448.1 (400 MHz, Methanol-d₄) δ 7.78-7.73 (m, 1H), 7.72-7.64 (m, 4H),7.49-7.43 (m, 2H), 5.07 (s, 2H), 4.50 (s, 2H), 4.20-4.12 (m, 1H),3.00-2.91 (m, 2H), 2.47-2.37 (m, 2H)

Example 47: Synthesis of Compound 339 1. Synthesis of Intermediate 47-2

This step followed the published method in Synlett 2007, No. 2, pp.0227-0230. Briefly, to a solution of 1-benzhydrylazetidin-3-one (1.84 g,7.76 mmol) and (S)-1-(4-(trifluoromethyl)phenyl)ethan-1-amine (1.47 g,7.76 mmol, 1.0 equiv.) in MeOH (10 mL) were added diphenylmethylisocyanide (1.50 g, 7.76 mmol, 1.0 equiv.) and 2-chloroacetic acid (733mg, 7.76 mmol, 1.0 equiv.) sequentially. The resulting mixture wasstirred at r.t. for 5 h, diluted with EA (150 mL), washed with saturatedaqueous NaHCO₃ (100 mL), saturated aqueous NH₄Cl (100 mL) and brine,dried over sodium sulfate, concentrated under reduced pressure, andpurified by silica gel chromatography using EA/Hex (1/4) to provide 2.0g (36%) of(S)—N,1-dibenzhydryl-3-(2-chloro-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamido)azetidine-3-carboxamide. LRMS (APCI) m/z 696.3 (M+H).

2. Synthesis of Intermediate 47-3

To a solution of(S)—N,1-dibenzhydryl-3-(2-chloro-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamido)azetidine-3-carboxamide(1.97 g, 2.83 mmol) in THF (25 mL) cooled to 0° C. with an ice bath wasadded LHMDS (3.39 mL of 1.0 M in THF, 3.39 mmol, 1.2 equiv.) dropwiseover 5 minutes. The resulting mixture was stirred at 0° C. for 1 h,quenched with saturated aqueous NH₄Cl (30 mL), and diluted with EA (75mL). The organic phase was washed with brine, dried over sodium sulfate,concentrated, and purified by silica gel chromatography using EA/HE(15/85) to provide 1.1 g (59%) of(S)-2,8-dibenzhydryl-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione.LRMS (APCI) m/z 660.4 (M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 7.61 (d,J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.34-7.03 (m, 20H), 6.85 (s, 1H),5.84 (t, J=7.0 Hz, 1H), 4.12 (s, 1H), 3.76 (d, J=8.9 Hz, 1H), 3.71-3.59(m, 2H), 3.49 (d, J=8.8 Hz, 1H), 3.39 (t, J=9.1 Hz, 2H), 1.79 (d, J=7.1Hz, 3H).

3. Synthesis of Intermediate 47-4

To a solution of(S)-2,8-dibenzhydryl-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione(1.10 g, 1.66 mmol) in a mixture of MeOH (100 mL) and EA (100 mL) wereadded Pd(OH)₂ (20% on carbon, 1.3 g) and acetic acid (0.5 mL). Theresulting mixture was sparged with hydrogen for 5 minutes, heated at 50°C. under hydrogen (initially at 500 psi) for 20 h, filtered throughcelite, and concentrated under reduced pressure to provide 640 mg of(S)-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dioneacetate. LRMS (APCI) m/z 328.1 (M+H).

4. Synthesis of Intermediate 47-5

To a mixture of(S)-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dioneacetate (320 mg, 0.83 mmol) in DCM (10 mL) cooled to 0° C. with an icebath was added TEA (346 μL, 3.0 equiv.) and acetyl chloride (1.66 mL of1.0 M solution in DCM, 1.66 mmol, 2.0 equiv.) sequentially. The ice bathwas removed upon the completion of addition. The mixture was stirred atr.t. for 30 min, diluted with DCM (20 mL), and washed with saturatedaqueous NaHCO₃ (15 mL). The aqueous phase was extracted with DCM (20mL). The combined organic phases were dried over sodium sulfate andconcentrated. The mixture was suspended in Et₂O (10 mL), sonicated,filtered, and dried to provide 188 mg (61%) of(S)-2-acetyl-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione.LRMS (APCI) m/z 370.1 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 8.52 (s, 1H),7.67 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 5.1-5.30 (bs, 1H), 4.51(dd, J=36.1, 9.5 Hz, 1H), 4.40-4.24 (m, 1H), 4.18 (t, J=9.5 Hz, 1H),4.06-3.82 (m, 3H), 1.87 (dd, J=6.9, 3.5 Hz, 3H), 1.74 (d, J=23.2 Hz,3H).

5. Synthesis of Compound 339

To a mixture of(S)-2-acetyl-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione(102 mg, 0.28 mmol), Cut (26 mg, 0.14 mmol, 0.5 equiv.), K₂CO₃ (115 mg,0.83 mmol, 3.0 equiv.) and 3-fluoro-4-iodobenzonitrile (136 mg, 0.55mmol, 2.0 equiv.) in a tube were added 1,4-dioxane (1.5 mL) andN,N-dimethylethylenediamine (15 μL, 0.14 mmol, 0.5 equiv.). The mixturewas purged with N₂, sealed, heated at 115° C. for 18 h, cooled to r.t.,and filtered through celite. The solid was washed with 1,4-dioxane (20mL). The filtrate was evaporated in vacuo and purified with reversephase HPLC using ACN/water (both with 0.1% formic acid with a gradientfrom 10 to 100%; Phenomenex Gemini 5 micron C18 column). The collectedfractions provided a mixture which was purified again by silica gelchromatography using EA/Hex (3/7) and MeOH/DCM (1/9) as eluents toprovide 24 mg (18%) of(S)-4-(2-acetyl-6,9-dioxo-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile.LRMS (APCI) m/z 489.2 (M+H). ¹H NMR (400 MHz, Methanol-d₄) δ 7.83-7.61(m, 7H), 5.4-5.6 (bs, 1H), 4.82-4.43 (m, 5H), 4.37 (d, J=11.0 Hz, 1H),2.03 (t, J=6.8 Hz, 3H), 1.88 (d, J=23.1 Hz, 3H).

Example 48: Synthesis of Compound 340

Method analogous to Example 47 was used with the only exception that1-bromo-4-chloro-2-fluorobenzene was used in step 5 instead of3-fluoro-4-iodobenzonitrile.

Example 49: Synthesis of Compound 341 1. Synthesis of Intermediate 49-2

To a mixture of 4-trifluoromethylbenzyl amine (1.2 g, 7.0 mmol, 1.1equiv) and 1-benzhydrylazetidin-3-one (1.5 g, 6.3 mmol, 1.0 equiv) inMeOH (30 mL) were added (isocyanomethylene)dibenzene (1.3 g, 7.0 mmol,1.1 equiv) and 2-chloropropionic acid (0.76 g, 7.0 mmol, 1.1 equiv). Theresulting mixture was stirred at r.t. for 15 h, concentrated underreduced pressure, and purified by silica gel chromatography using EA/HE(1/3) as eluents to provide 1.8 g (41%) ofN,1-dibenzhydryl-3-(2-chloro-N-(4-(trifluoromethyl)benzyl)propanamido)azetidine-3-carboxamide.LRMS (ES) m/z 696.3 (M+H).

2. Synthesis of Intermediate 49-3

To a solution ofN,1-dibenzhydryl-3-(2-chloro-N-(4-(trifluoromethyl)benzyl)propanamido)azetidine-3-carboxamide (1.8 g, 2.6 mmol, 1.0 equiv) in THF(200 mL) cooled to 0° C. with an ice bath was added LHMDS (1 M in THF,3.1 mL, 3.1 mmol, 1.2 equiv) dropwise over 10 min. The resulting mixturewas stirred at 0° C. for 2 h, quenched with MeOH (5 mL), andconcentrated onto SiO₂ (20 g). The mixture was purified by silica gelchromatography using EA/HE (gradient from 0-100%) to provide 1.2 g (70%)of2,8-dibenzhydryl-7-methyl-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione.LRMS (ES) m/z 660.3 (M+H).

3. Synthesis of Intermediate 49-4

To a solution of2,8-dibenzhydryl-7-methyl-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione(1.2 g, 1.8 mmol, 1.0 equiv) in EtOAc (100 mL) was added Pd(OH)₂ (20% oncarbon, 6 g). The resulting mixture was sparged with hydrogen for 10min, heated at 50° C. under hydrogen (initially at 500 psi) for 60 h,cooled to r.t., filtered through celite, and concentrated under reducedpressure to provide 887 mg of8-benzhydryl-7-methyl-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dioneas a mixture. LRMS (ES) m/z 494.2 (M+H).

4. Synthesis of Intermediate 49-5

To a solution of8-benzhydryl-7-methyl-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione(887 mg, 1.8 mmol, 1.0 equiv.) in DCM (20 mL) were added TEA (1 mL) andacetyl chloride (1 M in DCM, 5 mL, 5.0 mmol, 2.8 equiv). The resultingmixture was stirred at r.t. for 2 h, concentrated under reducedpressure, and purified by silica gel chromatography using EtOAc (100%)and MeOH/DCM (1/4) as eluents to provide 963 mg of2-acetyl-8-benzhydryl-7-methyl-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dioneas a mixture. LRMS (ES) m/z 536.2 (M+H).

5. Synthesis of Intermediate 49-6

To a solution of2-Acetyl-8-benzhydryl-7-methyl-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione(963 mg, 1.8 mmol, 1.0 equiv) in EtOAc (100 mL) was added Pd(OH)₂ (20%on carbon, 6 g). The resulting mixture was sparged with hydrogen for 10min, heated at 50° C. under hydrogen (initially at 600 psi) for 15 h,cooled to r.t., filtered through celite, concentrated under reducedpressure, and purified by silica gel chromatography using EtOAc (100%)and MeOH/DCM (1/4) as eluents to provide 200 mg of2-acetyl-7-methyl-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione.LRMS (ES) m/z 370.2 (M+H).

6. Synthesis of Compound 341

To a mixture of copper iodide (26 mg, 0.14 mmol, 0.5 equiv), potassiumcarbonate (112 mg, 0.81 mmol, 3.0 equiv),1-bromo-4-chloro-2-fluorobenzene (102 mg, 0.49 mmol, 1.8 equiv), and2-acetyl-7-methyl-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione(200 mg, 0.27 mmol, 1.0 equiv) in a vial were added 1.4-dioxane (3 mL)and N,N′-dimethylethylene diamine (15 μL, 0.14 mmol, 0.5 equiv). Thevial was sealed and the mixture was heated at 100° C. for 15 h. Themixture was cooled to r.t., filtered through celite, concentrated underreduced pressure, and purified with reverse phase HPLC (Phenomenex,gemini 5u C18 150×21.2 mm, 10-70% acetonitrile in water both with 0.1%formic acid gradient over 40 min) to provide 1.4 mg (1%) of2-acetyl-8-(4-chloro-2-fluorophenyl)-7-methyl-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione.LRMS (ES) m/z 498.1 (M+H). ¹H-NMR (Methanol-d₄, 400 MHz, ppm) δ 7.71 (d,J=8.1 Hz, 2H), 7.55 (dd, J=8.1, 4.8 Hz, 3H), 7.50-7.44 (m, 1H), 7.40(dt, J=8.5, 1.6 Hz, 1H), 5.22 (d, J=16.8 Hz, 1H), 5.11-5.01 (m, 1H),4.68-4.41 (m, 4H), 4.26 (t, J=11.5 Hz, 1H), 1.88 (d, J=6.1 Hz, 3H), 1.45(d, J=7.0 Hz, 3H).

Example 50: Synthesis of Compound 278 1. Synthesis of Intermediate 50-2

To a solution of ethyl 1-aminocyclopropane-1-carboxylate hydrochloride(0.5 g, 3.0 mmol, 1.0 equiv) in a mixture of THF (50 mL) and DCE (10 mL)was added 4-trifluoromethylbenzaldehyde (0.79 g, 4.5 mmol, 1.5 equiv).To the mixture stirred at r.t. for 15 min were added STAB (1.9 g, 9.1mmol, 3.0 equiv) and AcOH (5 mL). The mixture was stirred at r.t. for 15h, evaporated under reduced pressure, and partitioned between DCM (60mL) and saturated aqueous sodium bicarbonate (60 mL). The layers wereseparated and the aqueous phase was extracted with DCM (25 mL). Thecombined organic phases were dried over sodium sulfate, filtered throughcelite, and concentrated under reduced pressure to provide ethyl1-((4-(trifluoromethyl)benzyl)amino)cyclopropane-1-carboxylate as aviscous oil.

2. Synthesis of Intermediate 50-3

To a solution of ethyl1-((4-(trifluoromethyl)benzyl)amino)cyclopropane-1-carboxylate (861 mg,3.0 mmol, 1.0 equiv) in DCM (50 mL) were added TEA (1.5 g, 15.1 mmol,5.0 equiv) and chloroacetyl chloride (0.68 g, 6.0 mmol, 2.0 equiv). Themixture was stirred at r.t. for 2 h before pouring into water (50 mL).The organic phase was separated, dried over MgSO₄, and concentratedunder reduced pressure to give ethyl1-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)cyclopropane-1-carboxylate.

3. Synthesis of Intermediate 50-4

To a solution of ethyl1-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)cyclopropane-1-carboxylate (1.1 g, 3.0 mmol) in MeOH (5 mL) was addedNH₃ in MeOH (7 N, 5 mL). The resulting mixture was heated at 80° C. in asealed tube for 15 h, cooled to r.t., concentrated under reducedpressure, and purified by silica gel chromatography using EA/HE(gradient from 0-100%) and MeOH/DCM (3/7) to provide4-(4-(trifluoromethyl) benzyl)-4,7-diazaspiro[2.5]octane-5,8-dione. LRMS(ES) m/z 299.1 (M+H).

4. Synthesis of Compound 278

To a mixture of copper iodide (33 mg, 0.18 mmol, 0.5 equiv), potassiumcarbonate (146 mg, 1.1 mmol, 3.0 equiv), 4-bromo-3-fluorobenzonitrile(126 mg, 0.63 mmol, 1.8 equiv), and4-(4-(trifluoromethyl)benzyl)-4,7-diazaspiro[2.5]octane-5,8-dione (200mg, 0.35 mmol, 1.0 equiv) in a vial were added 1,4-dioxane (16 mL) andN,N′-dimethylethylene diamine (19 μL, 0.18 mmol, 0.5 equiv). The vialwas sealed and the mixture was heated at 100° C. for 15 h. The mixturewas cooled to r.t., filtered through celite, concentrated under reducedpressure, and purified with reverse phase HPLC (Phenomenex, gemini 5uC18 150×21.2 mm, 10-100% acetonitrile in water both with 0.1% formicacid gradient over 40 min) to provide 40 mg (27%) of4-(5,8-dioxo-4-(4-(trifluoromethyl)benzyl)-4,7-diazaspiro[2.5]octan-7-yl)-3-fluorobenzonitrile.LRMS (ES) m/z 418.1 (M+H). ¹H-NMR (Methanol-d₄, 400 MHz, ppm) δ 7.76(dd, J=10.2, 1.6 Hz, 1H), 7.71-7.62 (m, 4H), 7.48 (d, J=8.0 Hz, 2H),4.74 (s, 2H), 4.66 (s, 2H), 1.55-1.30 (m, 4H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 278:

Compound No. LRMS (ES) m/z 269 M + H = 436.1 270 M + H = 445.1 271 M + H= 427.1 272 M + H = 441.1 273 M + H = 429.1 274 M + H = 443.1 277 M + H= 401.0 279 M + H = 420.1 280 M + H = 434.1 281 M + H = 457.1 282 M + H= 448.1 286 M + H = 448.0

5. Separation of Enantiomers

The racemic compound was separated by Chiral-HPLC with the followingconditions (Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 um; Mobile PhaseA: Hex-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient:30 B to 30 B in 10 min; 220/254 nm) to give a first eluting peak and asecond eluting peak.

The following compounds were separated by the method described above:

Compound No. LRMS (ES) m/z 275 M + H = 415.1 276 M + H = 415.1 283 M + H= 434.0 285 M + H = 478.1 287 M + H = 422.1

Example 51: Synthesis of Compound 284 1. Synthesis of Intermediate 51-2

To a solution of (S)-methyl-2-amino-cyclobutylacetate HCl (0.50 g, 2.8mmol, 1.0 equiv) in dry MeOH (16 mL) were added4-(trifluoromethyl)benzaldehyde (0.42 mL, 3.1 mmol, 1.1 equiv) andacetic acid (0.32 mL, 5.6 mmol, 2.0 equiv). To the mixture stirred for 1h was added sodium cyanoborohydride (0.306 g, 4.87 mmol, 1.8 equiv). Themixture was continued to stir overnight, diluted with water, andextracted with DCM three times. The combined organic layers were driedover magnesium sulfate, filtered, evaporated, and purified by silica gelchromatography through silica gel using EA/HE (gradient from 0-20%) aseluents to give 138 mg (16%) of methyl(S)-2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)amino)acetate as a clearcolorless oil. LRMS (ES) m/z 302 (M+H).

2. Synthesis of Intermediate 51-3

To a solution of methyl(S)-2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)amino) acetate (138 mg,0.46 mmol, 1.0 equiv) in DCM (2 mL) cooled to 0° C. were added TEA (0.38mL, 2.8 mmol, 6.0 equiv) and chloroacetyl chloride (0.15 mL, 1.8 mmol,4.0 equiv) dropwise. The mixture was stirred at 0° C. for 1 h, dilutedwith saturated sodium bicarbonate, extracted DCM twice. The combinedorganic layers were dried over magnesium sulfate, filtered, evaporated,and purified by silica gel chromatography through silica gel using EA/HE(gradient from 0-30%) as eluents to give 0.162 g (93%) of methyl(S)-2-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-2-cyclobutylacetateas a clear yellow oil. LRMS (ES) m/z 378 (M+H).

3. Synthesis of Intermediate 51-4

To a solution of methyl(S)-2-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-2-cyclobutylacetate(162 mg, 0.43 mmol, 1.0 equiv) in dry methanol (1.2 mL) was added 7 Mammonia in methanol (1.2 mL, 8.6 mmol, 20 equiv). The mixture wassealed, heated at 80° C. overnight, diluted with water, and extractedtwice with EA. The combined organic layers were dried over magnesiumsulfate, filtered, evaporated, and purified by silica gel chromatographythrough silica gel using MeOH/DCM (gradient from 0-10%) as eluents togive 123 mg (88%) of(S)-6-cyclobutyl-1-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione as aclear colorless oil. LRMS (ES) m/z 327 (M+H). ¹H NMR (400 MHz, MethyleneChloride-d₂) δ 7.70-7.61 (m, 2H), 7.45-7.37 (m, 2H), 6.63-6.46 (m, 1H),5.38-5.34 (m, 1H), 4.17-4.04 (m, 2H), 4.00-3.90 (m, 1H), 3.72-3.65 (m,1H), 2.85-2.71 (m, 1H), 2.12-1.66 (m, 6H).

4. Synthesis of Compound 284

To a mixture of 4-bromo-3-fluorobenzonitrile (68 mg, 0.34 mmol, 1.8equiv), copper (I) iodide (1.8 mg, 0.09 mmol, 0.50 equiv), and potassiumcarbonate (78 mg, 0.56 mmol, 3.0 equiv) in vacuum-nitrogen purged vialwere added N,N′-dimethylethylenediamine (0.010 mL, 0.094 mmol, 0.50equiv) and (S)-6-cyclobutyl-1-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione (61 mg, 0.19 mmol, 1.0 equiv) in dry dioxane (1mL). The vial was sealed and the mixture was heated at 100° C.overnight. The mixture was cooled to r.t., filtered, and purified byreverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm, 10-90%acetonitrile in water both with 0.1% formic acid gradient over 25 min)to give 39 mg (47%) of(S)-4-(3-cyclobutyl-2,5-dioxo-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrileas a clear colorless oil. LRMS (ES) m/z 446 (M+H). ¹H NMR (400 MHz,Methanol-d₄) δ 7.77-7.72 (m, 1H), 7.71-7.62 (m, 4H), 7.55-7.50 (m, 2H),5.26-5.18 (m, 1H), 4.83-4.76 (m, 1H), 4.43-4.36 (m, 1H), 4.25-4.17 (m,1H), 4.02-3.97 (m, 1H), 3.04-2.91 (m, 1H), 2.16-1.75 (m, 6H).

Example 52: Synthesis of Compound 528 1. Synthesis of Intermediate 52-1

To a solution of tert-butyl6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(450 mg, 1.1 mmol, 1 equiv) in NMP (5 mL) was added NaHMDS (0.82 mL, 1.6mmol, 1.5 equiv, 2 M in THF) dropwise at 0° C. After stirring at r.t.for 30 min, to the mixture was added 5-chloro-2,3-difluoropyridine (243mg, 1.6 mmol, 1.5 equiv). The resulting mixture was stirred at 80° C.for 5 h and cooled to 0° C. The reaction was quenched with water (10 mL)at 0° C. and extracted with EtOAc (20 mL). The organic layer was washedtwice with brine (20 mL), dried over anhydrous Na₂SO₄, concentratedunder reduced pressure, and purified by silica gel column chromatographyusing with PE/EA (5/1) as eluent to afford 350 mg of tert-butyl8-(5-chloro-3-fluoropyridin-2-yl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(Intermediate 52-1) as a yellow oil. LRMS (ES) m/z 487 (M+H-56).

2. Synthesis of Intermediate 52-2

To a solution of tert-butyl8-(5-chloro-3-fluoropyridin-2-yl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(350 mg, 0.6 mmol, 1 equiv) in DCM (3 mL) was added2,2,2-trifluoroacetic acid (1 mL). The resulting mixture was stirred atr.t. for 3 h and concentrated under reduced pressure to give 300 mg of8-(5-chloro-3-fluoropyridin-2-yl)-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-6,9-dionetrifluoroacetate (Intermediate 52-2) as a yellow oil. LRMS (ES) m/z 443(M+H).

3. Synthesis of Compound 528

To a solution of8-(5-chloro-3-fluoropyridin-2-yl)-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-6,9-dionetrifluoroacetate (300 mg, 0.6 mmol, 1 equiv) in DCM (5 mL) were addedacetyl acetate (85 mg, 0.8 mmol, 1.5 equiv) and TEA (168 mg, 1.67 mmol,3.0 equiv). The resulting mixture was stirred at r.t. for 2 h,concentrated under vacuum, and purified by Prep-HPLC with the followingconditions (SHIMADZU (HPLC-01)): Column, XBridge Prep OBD C18 Column,30*150 mm 5 um; mobile phase, Water (10 mM, NH₄HCO₃) and ACN (31%gradient up to 49% in 8 min); Detector, UV254 nm) to afford 90 mg of2-acetyl-8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione(Compound 528) as a white solid. LRMS (ES) m/z 485 (M+H). ¹H NMR (400MHz, Methanol-d₄) δ 8.43 (d, J=1.9 Hz, 1H), 7.98 (dt, J=9.3, 2.0 Hz,1H), 7.77-7.67 (m, 2H), 7.56 (d, J=8.0 Hz, 2H), 5.13 (s, 2H), 4.71 (d,J=10.1 Hz, 3H), 4.50 (d, J=10.2 Hz, 2H), 4.25 (d, J=10.9 Hz, 1H), 1.87(s, 3H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 528:

Compound No. LRMS (ES) m/z 529 M + H = 472 530 M + H = 476 556 M + H =465 619 M + H = 479 620 M + H = 485

Example 53: Synthesis of Compound 531 1. Synthesis of Compound 531

To a solution of4-(6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile(35.0 mg, 0.08 mmol, 1.0 equiv) in DMF (1.0 mL) were added2-(methylamino)benzoic acid (12.0 mg, 0.08 mmol, 1.0 equiv), HATU (37.0mg, 0.1 mmol, 1.2 equiv) and DIEA (21.0 mg, 0.2 mmol, 2.0 equiv). Theresulting mixture was stirred at r.t. for 2 h. The solution was purifiedby Prep-HPLC with the following conditions (SHIMADZU (HPLC-01)): Column,XBridge Shield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, Water (10mM, NH₄HCO₃) and ACN (30% gradient up to 50% in 8 min); Detector,uv254/220 nm) to afford 20 mg of3-fluoro-4-(2-(2-(methylamino)benzoyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)benzonitrile(Compound 531) as a white solid. LRMS (ES) m/z 566 (M+H). ¹H NMR (400MHz, Methanol-d₄) δ 7.79 (d, J=9.8 Hz, 1H), 7.76-7.65 (m, 4H), 7.58 (d,J=8.1 Hz, 2H), 7.31 (t, J=8.0 Hz, 1H), 7.15 (dd, J=7.7, 1.5 Hz, 1H),6.72 (d, J=8.4 Hz, 1H), 6.57 (t, J=7.4 Hz, 1H), 5.17 (s, 2H), 4.68 (d,J=10.6 Hz, 2H), 4.57 (s, 2H), 4.46 (d, J=10.6 Hz, 2H), 2.83 (s, 3H).

Example 54: Synthesis of Compound 536 1. Synthesis of Compound 536

To a solution of4-(6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile(100.0 mg, 0.23 mmol, 1.0 equiv) in dioxane (2.0 mL) were added3-bromo-N-methylaniline (50.0 mg, 0.27 mmol, 1.2 equiv), Pd₂(dba)₃ (24.0mg, 0.03 mmol, 0.11 equiv), X-phos (22.0 mg, 0.05 mmol, 0.2 equiv) andCs₂CO₃ (151.0 mg, 0.5 mmol, 2.0 equiv). The resulting mixture wasstirred at 80° C. for 3 h under nitrogen atmosphere, cooled to rt, andpurified by Prep-TLC (PE/EtOAc 1/1) to afford a mixture, which waspurified by Prep-HPLC with the following conditions (SHIMADZU(HPLC-01)): Column, Xselect CSH OBD Column 30*150 mm 5 um; mobile phase,Water (10 mM, NH₄HCO₃) and ACN (45% gradient up to 80% in 9 min);Detector, UV254/220 nm) to afford 43 mg of3-fluoro-4-[2-[3-(methylamino)phenyl]-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan-8-yl]benzonitrile(Compound 536) as an off-white solid. LRMS (ES) m/z 538 (M+H). ¹H NMR(300 MHz, Chloroform-d) δ 7.69-7.38 (m, 7H), 7.07 (t, J=7.9 Hz, 1H),6.17 (d, J=8.0 Hz, 1H), 5.87 (d, J=7.9 Hz, 1H), 5.70 (s, 1H), 5.28 (s,2H), 4.53 (d, J=8.3 Hz, 2H), 4.45 (s, 2H), 4.12 (d, J=8.3 Hz, 2H), 2.83(s, 3H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 536:

Compound No. LRMS (ES) m/z 535 M + H = 538 538 M + H = 538

Example 55: Synthesis of Compound 539 1. Synthesis of Intermediate 55-1

To a solution of methyl 3-iodobenoate (250.0 mg, 1.0 mmol, 1.0 equiv) ina mixture of EtOH (4.0 mL) and water (1.0 mL) was added NaOH (115 mg,3.0 mmol, 3.0 equiv). The mixture was stirred at 60° C. for 2 h, cooledto rt, acidified to pH 3, and extracted with EA (20 mL). The organiclayer was washed with brine twice, dried over Na₂SO₄, and concentratedunder reduced pressure to afford 200 mg of 3-iodobenzoic acid(Intermediate 55-1) as an off-white solid. LRMS (ES) m/z 249 (M+H).

2. Synthesis of Intermediate 55-2

To a solution of methyl 3-iodobenoic acid (250.0 mg, 0.81 mmol, 1.0equiv) in DMF (3.0 mL) were added methylamine (0.6 mL, 1.2 mmol, 1.5equiv, 2M/THF), HATU (368 mg, 1.0 mmol, 1.2 equiv.), and DIEA (208 mg,1.6 mmol, 2.0 equiv.). The mixture was stirred at rt overnight, dilutedwith water, and extracted with EA (20 mL). The organic layer was washedwith brine twice, dried over Na₂SO₄, concentrated under reducedpressure, and purified by silica gel column chromatography using PE/EA(4/1) as eluent to afford 200 mg of 3-iodo-N-methylbenzamide(Intermediate 55-2) as an off-white solid. LRMS (ES) m/z 262 (M+H).

3. Synthesis of Compound 539

To a solution of4-(6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile(100.0 mg, 0.23 mmol, 1.0 equiv) in dioxane (2.0 mL) were added3-iodo-N-methylbenzamide (90.0 mg, 0.35 mmol, 1.5 equiv), Pd₂(dba)₃(24.0 mg, 0.03 mmol, 0.11 equiv), X-phos (22.0 mg, 0.05 mmol, 0.2 equiv)and Cs₂CO₃ (151.0 mg, 0.5 mmol, 2.0 equiv). The resulting mixture wasstirred at 90° C. for 2 h under nitrogen atmosphere, cooled to rt,filtered, and purified by Prep-TLC (PE/EtOAc 1/8) to afford a mixture,which was further purified by Prep-HPLC with the following conditions(SHIMADZU (HPLC-01)): Column, Xselect CSHOBD Column 30*150 mm 5 um,mobile phase, Water (10 mM, NH₄HCO₃) and ACN (35% gradient up to 58% in10 min); Detector, UV254/220 nm) to afford 45 mg of3-(8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-2-yl)-N-methylbenzamide(Compound 539) as a white solid. LRMS (ES) m/z 566 (M+H). 1H NMR (400MHz, Methanol-d₄) δ 7.82-7.75 (m, 1H), 7.78-7.68 (m, 2H), 7.68 (d, J=8.1Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.30 (t, J=7.8 Hz, 1H), 7.21 (dt,J=7.8, 1.3 Hz, 1H), 6.92 (t, J=2.0 Hz, 1H), 6.68-6.61 (m, 1H), 5.29 (s,2H), 4.60 (s, 2H), 4.48 (d, J=8.7 Hz, 2H), 4.27 (d, J=8.7 Hz, 2H), 2.90(s, 3H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 539:

Compound No. LRMS (ES) m/z 532 M + H = 567 533 M + H = 567 534 M + H =567 537 M + H = 566 540 M + H = 566

Example 56: Synthesis of Compound 541 1. Synthesis of Intermediate 56-1

To a solution of methyl 2-amino-4-bromobenzoate (1.5 g, 6.5 mmol, 1.0equiv.) in DCM (15.0 mL) were added TEA (2.0 g, 19.8 mmol, 3.0 equiv.),DMAP (797 mg, 6.5 mmol, 1.0 equiv.), and (Boc)₂O (1.7 g, 7.8 mmol, 1.2equiv.) at 0° C. The mixture was stirred at rt overnight, diluted withDCM (50 mL), washed with brine (50 mL) twice, dried over Na₂SO₄,concentrated under reduced pressure, and purified by silica gelchromatography using PE/EA as eluent to afford 1.1 g of methyl4-bromo-2-[[(tert-butoxy)carbonyl]amino]benzoate (Intermediate 56-1) asa white solid. LRMS (ES) m/z 274 (M+H-56).

2. Synthesis of Intermediate 56-2

To a solution of methyl 4-bromo-2-[[(tert-butoxy)carbonyl]amino]benzoate(1.1 g, 3.3 mmol, 1.0 equiv.) in DMF (15.0 mL) was added NaH (60% inmineral oil, 160 mg, 4.0 mmol, 1.2 equiv.) at 0° C. After stirring for30 min at 0° C., to this mixture was added iodomethane (521 mg, 3.7mmol, 1.1 equiv.). The mixture was then stirred at rt overnight,quenched with water, and extracted with EA (100 mL). The organic layerwas washed with saturated sodium bicarbonate solution (20 mL) once andbrine (20 mL) twice, dried over Na₂SO₄, concentrated under reducedpressure, and purified by silica gel chromatography using PE/EA (50/1)as eluent to afford 800 mg of methyl4-bromo-2-[[(tert-butoxy)carbonyl](methyl)amino]benzoate (Intermediate56-2) as a yellow oil. LRMS (ES) 288 m/z (M+H-56).

3. Synthesis of Intermediate 56-3

To a solution of methyl4-bromo-2-[[(tert-butoxy)carbonyl](methyl)amino]benzoate (400 mg, 3.3mmol, 1.0 equiv.) in DCM (4.0 mL) was added TFA (1.0 mL). The mixturewas stirred at rt for 2 h, adjusted pH to 9 with sat sodium bicarbonate,and extracted with EA (20 mL). The organic layer was washed with brine(20 mL) twice, dried over Na₂SO₄, and concentrated under reducedpressure to afford methyl 4-bromo-2-(methylamino)benzoate (Intermediate56-3) as a yellow oil. LRMS (ES) 244 m/z (M+H).

4. Synthesis of Compound 541

To a solution of4-(6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile(100.0 mg, 0.2 mmol, 1.0 equiv) in dioxane (2.0 mL) were added methyl4-bromo-2-(methylamino)benzoate (80.0 mg, 0.3 mmol, 1.4 equiv),Pd₂(dba)₃CHCl₃ (24.0 mg, 0.023 mmol, 0.10 equiv), X-phos (22.0 mg, 0.05mmol, 0.2 equiv), and Cs₂CO₃ (151.0 mg, 0.5 mmol, 2.0 equiv). Theresulting mixture was stirred at 80° C. for 2 h under nitrogenatmosphere, cooled to r.t., and purified by Prep-TLC (PE/EtOAc 1:1) toafford a mixture, which was purified by Prep-HPLC with the followingconditions (SHIMADZU (HPLC-01)): Column, XBridge Prep OBD C18 Column,30*150 mm 5 um; mobile phase, Water (10 mM NH₄HCO₃) and ACN (50%gradient up to 80% in 8 min); Detector uv 254 nm) to afford 80 mg ofmethyl4-(8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-2-yl)-2-(methylamino)benzoate(Compound 541) as a white solid. LRMS (ES) m/z 596 (M+H). ¹H-NMR: (300MHz, Methanol-d₄) δ 7.83-7.62 (m, 6H), 7.56 (d, J=8.1 Hz, 2H), 5.73 (dd,J=8.6, 2.2 Hz, 1H), 5.54 (d, J=2.2 Hz, 1H), 5.22 (s, 2H), 4.59 (s, 2H),4.52 (d, J=9.1 Hz, 2H), 4.27 (d, J=9.0 Hz, 2H), 3.77 (s, 3H), 2.84 (s,3H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 541:

Compound No. LRMS (ES) m/z 542 M + H = 595 543 M + H = 596 544 M + H =596 545 M + H = 595 546 M + H = 596 547 M + H = 595

Example 57: Synthesis of Compound 550 1. Synthesis of Intermediate 57-1

To a stirred solution of ethyl 1-aminocyclopropane-1-carboxylatehydrochloride (1.14 g, 7 mmol, 1.2 equiv) and4-(trifluoromethyl)benzaldehyde (1.0 g, 6 mmol, 1.0 equiv) in DCE (20mL) was added acetic acid (0.69 g, 11 mmol, 2.0 equiv). After stirringat rt for 5 min, to the mixture was added STAB (1.83 g, 9 mmol, 1.5equiv). The resulting mixture was stirred for overnight at rt, dilutedwith DCM (20 m L), and washed with brine (20 mL), dried over anhydrousNa₂SO₄, and concentrated under reduced pressure to afford 1.48 g (73%)of ethyl 1-((4-(trifluoromethyl)benzyl)amino)cyclopropane-1-carboxylate(Intermediate 57-1) as a yellow oil. LRMS (ES) m/z 274 (M+H).

2. Synthesis of Intermediate 57-2

To a stirred solution of ethyl1-((4-(trifluoromethyl)benzyl)amino)cyclopropane-1-carboxylate (1.48 g,5.4 mmol, 1.0 equiv) in DCM (90 mL) cooled to 0° C. were added K₂CO₃(16.2 mL, 0.5 M in water, 1.5 equiv) and 2-bromoacetyl bromide (1.31 g,6 mmol, 1.2 equiv) dropwise. The resulting mixture was stirred foradditional 3 h at rt, washed with brine (80 mL), dried over anhydrousNa₂SO₄, concentrated under reduced pressure to afford 1.8 g (82%) ofethyl1-(2-bromo-N-(4-(trifluoromethyl)benzyl)acetamido)cyclopropane-1-carboxylate(Intermediate 57-2) as a yellow oil. LRMS (ES) m/z 394 (M+H).

3. Synthesis of Intermediate 57-3

To a stirred solution of ethyl1-(2-bromo-N-(4-(trifluoromethyl)benzyl)acetamido)cyclopropane-1-carboxylate(1.79 g, 4.4 mmol, 1.0 equiv) in MeOH (5 mL) was added ammonia (25.0 mL,7M in MeOH). The resulting mixture was stirred for additional 1.5 h atroom temperature, concentrated under reduced pressure, and trituratedwith EA (10 mL) to afford 1.0 g (76%) of4-(4-(trifluoromethyl)benzyl)-4,7-diazaspiro[2.5]octane-5,8-dione(Intermediate 57-3) as a yellow solid. LRMS (ES) m/z 299 (M+H).

4. Synthesis of Compound 550

To a stirred solution of4-(4-(trifluoromethyl)benzyl)-4,7-diazaspiro[2.5]octane-5,8-dione (300.0mg, 1.0 mmol, 1.0 equiv) in ACN (3 mL) was added Cs₂CO₃ (651.0 mg, 2.0mmol, 2.0 equiv). After stirring for 5 min at rt, to the mixture wasadded 5-chloro-2,3-difluoropyridine (179.3 mg, 1.2 mmol, 1.2 equiv). Theresulting mixture was stirred for 2 days at 80° C., cooled to r.t,filtered to remove Cs₂CO₃, concentrated under reduced pressure, andpurified by Prep-HPLC with the following conditions: (SHIMADZU(HPLC-01)): Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm;mobile phase, Water (10 mM NH₄HCO_(3+0.1)% NH₃.H₂O) and ACN (41%gradient up to 71% in 8 min); Detector, UV 254 nm) to afford 6.7 mg (2%)of7-(5-chloro-3-fluoropyridin-2-yl)-4-(4-(trifluoromethyl)benzyl)-4,7-diazaspiro[2.5]octane-5,8-dione(Compound 550) as a white solid. LRMS (ES) m/z 428 (M+H). ¹H NMR (300MHz, DMSO-d₆) δ 8.48 (d, J=2.1 Hz, 1H), 8.25 (dd, J=9.6, 2.1 Hz, 1H),7.73 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 4.67 (s, 4H), 1.34 (d,J=4.4 Hz, 4H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 550:

Compound No. LRMS (ES) m/z 548 M + H = 442 554 M + H = 444 555 M + H =456 577 M + H = 394 616 M + H = 408 629 M + H = 473 632 M + H = 439 660M + H = 406

Example 58: Synthesis of Compound 574 1. Synthesis of Intermediate 58-1

To a solution of 3-(benzyloxy)cyclobutan-1-one (1.80 g, 10.215 mmol,1.07 equiv) in 2,2,2-trifluoroethanol (15 mL) was added1-(4-trifluoromethyl)phenyl)methanamine (1.9 g, 10.8 g, 1.1 equiv.).After stirring at r.t. for 5 min, to this resulting mixture were added5-chloro-3-fluoro-2-isocyanopyridine (1.5 g, 9.6 mmol, 1.0 equiv) andchloroacetic acid (994.0 mg, 10.5 mmol, 1.1 equiv). The resultingmixture was stirred at r.t. overnight, concentrated under reducedpressure, and purified by C18 column, eluted with water (0.5%NH₄HCO₃)/ACN (1:1) to afford 1.5 g of3-(benzyloxy)-N-(5-chloro-3-fluoropyridin-2-yl)-1-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxamide(Intermediate 58-1) as a yellow oil. LRMS (ES) m/z 584 (M+H).

2. Synthesis of Intermediate 58-2

To a solution of3-(benzyloxy)-N-(5-chloro-3-fluoropyridin-2-yl)-1-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxamide(1.4 g, 2.4 mmol, 1.0 equiv) in DMF (15.0 mL) at r.t was added K₂CO₃(994 mg, 7.1 mmol, 3.0 equiv). The mixture was stirred at 60° C. for 30min, cooled to rt, and diluted with water (30 mL). The precipitate wascollected, washed with water, and dried to afford 1.2 g of2-(benzyloxy)-8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-(trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane-6,9-dione(Intermediate 58-2). LRMS (ES) m/z 548 (M+H).

3. Synthesis of Intermediate 58-3

To a solution of2-(benzyloxy)-8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-(trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane-6,9-dione(500 mg, 0.9 mmol, 1.0 equiv.) in MeOH (5.0 mL) and THF (5.0 mL) wasadded Pd(OH)₂/C (20% wt., 250 mg). The mixture was stirred at rt for 1 hunder hydrogen (1 atm, hydrogen balloon), filtered through a celiteplug, and concentrated under reduced pressure to afford 400 mg of8-(5-chloro-3-fluoropyridin-2-yl)-2-hydroxy-5-(4-(trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane-6,9-dione(Intermediate 58-3) as a yellow oil. LRMS (ES) 458 m/z (M+H).

4. Synthesis of Compound 574

To a solution of8-(5-chloro-3-fluoropyridin-2-yl)-2-hydroxy-5-(4-(trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane-6,9-dione(200.0 mg, 0.4 mmol, 1.0 equiv) in DCM (3.0 mL) was added DAST (211 mg,1.3 mmol, 3.0 equiv.). The mixture was stirred at rt for 1 h,concentrated under reduced pressure, and purified by Prep-HPLC with thefollowing conditions (SHIMADZU (HPLC-01)): Column, Xselect CSH OBD C18Column, 30*150 mm 5 um; mobile phase, Water (0.1% FA) and ACN (10%gradient up to 50% in 9 min); Detector uv 254 nm) to afford 70 mg of8-(5-chloro-3-fluoropyridin-2-yl)-2-fluoro-5-(4-(trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane-6,9-dione(Compound 574) as a white solid. LRMS (ES) m/z 460 (M+H). ¹HNMR:(DMSO-d₆) δ 8.52 (d, J=2.1 Hz, 1H), 8.29 (dd, J=9.5, 2.1 Hz, 1H), 7.75(d, J=8.1 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 5.12-4.80 (m, 3H), 4.61 (s,2H), 2.99 (s, 2H), 2.71 (d, J=21.3 Hz, 2H).

Example 59: Synthesis of Compound 575 1. Synthesis of Intermediate 59-1

To a solution of 1-(4-chlorophenyl)methanamine (497.0 mg, 3.5 mmol, 1.1equiv) in 2,2,2-trifluoroethanol (10.0 mL) was added 3-oxetanone (254.0mg, 3.5 mmol, 1.1 equiv). After stirring at r.t. for 10 min, to theresulting mixture were added 5-chloro-3-fluoro-2-isocyanopyridine (500.0mg, 3.2 mmol, 1.0 equiv) and chloroacetic acid (331.0 mg, 3.5 mmol, 1.1equiv). The resulting mixture was stirred at r.t. overnight,concentrated under reduced pressure, and purified by C18 column, elutedwith water (0.05% NH₄HCO₃)/ACN (1:1) to afford 260 mg ofN-(5-chloro-3-fluoropyridin-2-yl)-3-[2-chloro-N-[(4-chlorophenyl)methyl]acetamido]oxetane-3-carboxamide(Intermediate 59-1) as a yellow solid. LRMS (ES) m/z 596 (M+H).

2. Synthesis of Compound 575

To a solution ofN-(5-chloro-3-fluoropyridin-2-yl)-3-[2-chloro-N-[(4-chlorophenyl)methyl]acetamido]oxetane-3-carboxamide(260.0 mg, 0.58 mmol, 1.0 equiv) in DMF (5.0 mL) was added potassiumcarbonate (242.0 mg, 1.7 mmol, 3.0 equiv). The resulting mixture wasstirred at 60° C. for 30 min and diluted with water (5 mL). Theprecipitates were collected by filtration, washed twice with water (5mL), and purified by Prep-HPLC: Column: Xselect CSH OBD Column 30*150 mm5 um; Mobile Phase A: Water (10 mM, NH₄HCO₃), Mobile Phase B: ACN; Flowrate: 60 mL/min; Gradient: 35% to 65% in 9 min; UV254 nm) to afford 60mg of8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-chlorobenzyl)-2-oxa-5,8-diazaspiro[3.5]nonane-6,9-dione(Compound 575) as a white solid. LRMS (ES) m/z 410 (M+H). ¹H NMR (300MHz, DMSO-d₆) δ 8.52 (d, J=2.1 Hz, 1H), 8.29 (dd, J=9.6, 2.2 Hz, 1H),7.47-7.32 (m, 4H), 5.08 (s, 2H), 4.93 (d, J=7.4 Hz, 2H), 4.75 (d, J=7.3Hz, 2H), 4.54 (s, 2H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 575:

Compound No. LRMS (ES) m/z 549 M + H = 430 551 M + H = 444.0 553 M + H =458 558 M − H = 422 572 M + H = 513.1 573 M + H = 446 576 M + H = 396610 M + H = 476 623 M + H = 472.0 624 M + H = 438 652 M + H = 468 663M + H = 434 665 M + H = 418.0 687 M + H = 502.0 688 M + H = 486.0 689M + H = 534 756 M + H = 494.0 757 M + H = 390.0 768 M + H = 428.0 799 M− H = 391 813 M + H = 484.0 814 M + H = 466.0 815 M + H = 434.1 816 M +H = 430.1

Example 60: Synthesis of Compound 857 1. Synthesis of Intermediate 60-1

To a stirred solution of methyl O-(tert-butyl)-L-serinate hydrochloride(1.0 g, 4.7 mmol, 1.0 equiv, 1.0 equiv) and4-(trifluoromethyl)benzaldehyde (818 mg, 4.7 mmol, 1.1 equiv) in DCE(10.0 mL) at r.t were added AcOH (564 mg, 9.4 mmol, 2. equiv) and STAB(1.50 g, 7.3 mmol, 1.5 equiv). The resulting mixture was stirred at roomtemperature for 2 h, neutralized to pH 7 with ammonium hydroxide, anddiluted with CH₂Cl₂ (50 mL). The organic layer was washed twice withbrine (50 mL), dried over anhydrous Na₂SO₄, and concentrated underreduced pressure to give 1.2 g of methylO-(tert-butyl)-N-(4-(trifluoromethyl)benzyl)-L-serinate (Intermediate60-1) as a light-yellow oil.

2. Synthesis of Intermediate 60-2

To a stirred solution of methylO-(tert-butyl)-N-(4-(trifluoromethyl)benzyl)-L-serinate (1.2 g, 3.6mmol, 1.0 equiv) and K₂CO₃ (0.5 M, 11 mL, 5.4 mmol, 1.5 equiv) in DCM(30 mL) at 0° C. was added bromoacetyl bromide (869 mg, 4.3 mmol, 1.2equiv) dropwise. The resulting mixture was stirred at room temperatureovernight, diluted with CH₂Cl₂ (50 mL). The organic layer was washedwith brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated underreduced pressure to give 1.3 g of methylN-(2-bromoacetyl)-O-(tert-butyl)-N-(4-(trifluoromethyl)benzyl)-L-serinate(Intermediate 60-2) as a light-yellow oil.

3. Synthesis of Intermediate 60-3

To a solution of ammonia (7 N in MeOH, 15.0 mL) was added methylN-(2-bromoacetyl)-O-(tert-butyl)-N-(4-(trifluoromethyl)benzyl)-L-serinate(1.3 g, 2.9 mmol, 1.0 equiv). The mixture was stirred at roomtemperature for 5 h, concentrated under reduced pressure, andtrituration with ethyl acetate (10 mL) to afford 500 mg of(S)-6-(tert-butoxymethyl)-1-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Intermediate 60-3) as a white solid.

4. Synthesis of Intermediate 60-4

To a stirred solution of(S)-6-(tert-butoxymethyl)-1-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(500.0 mg, 1.4 mmol, 1.0 equiv) in NMP (6 mL) at 0° C. was added NaHMDS(2 mL, 1 M in THF, 1.5 equiv) dropwise. After stirring at roomtemperature for 15 min, to the mixture was added5-chloro-2,3-difluoropyridine (314 mg, 2.1 mmol, 1.5 equiv). The mixturewas stirred at rt for 2 h and purified by reverse phase flashchromatography with the following conditions water (0.05%NH₄HCO₃):ACN=1:1 to afford 300 mg (44%) of3-(tert-butoxymethyl)-1-(5-chloro-3-fluoropyridin-2-yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Intermediate 60-4).

5. Synthesis of Compound 857

To a stirred solution of3-(tert-butoxymethyl)-1-(5-chloro-3-fluoropyridin-2-yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(300.0 mg, 0.6 mmol, 1.0 equiv) in DCM (24.0 mL) at room temperature wasadded TFA (6.0 mL). The resulting mixture was stirred at 40° C. for 2 h,concentrated under reduced pressure, and purified by Prep-HPLC with thefollowing conditions (SHIMADZU (HPLC-01)): Column, X Bridge Prep OBD C18Column, 30×150 mm 5 um; mobile phase A: Water (10 mM NH₄HCO₃+0.1%NH₃.H₂O) and mobile phase B: ACN (30% gradient up to 60% in 8 min);Detector UV 254/220 nm to afford 150 mg of1-(5-chloro-3-fluoropyridin-2-yl)-3-(hydroxymethyl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Compound 857).

6. Separation of Compound 857 Enantiomers: Enantiomers 857A and 857B

The racemic mixture of1-(5-chloro-3-fluoropyridin-2-yl)-3-(hydroxymethyl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(320 mg) was separated by Chiral HPLC with the following condition:Column, CHIRALPAK IG, 2 cm*25 cm L (5 um); mobile phase A: Hex (8 mMNH₃.MeOH) and mobile phase B: EtOH; Flow rate: 18 mL/min; (50% B/A for18 min); Detector, UV254/220 nm to afford 98 mg (first eluted peak) ofEnantiomer 857A and 91 mg (second eluted peak) of Enantiomer 857B.

Enantiomer 857A: LCMS (ES) m/z 432 (M+H). ¹H NMR (300 MHz, DMSO-d₆) δ8.48 (t, J=2.2 Hz, 1H), 8.24 (dt, J=9.5, 2.3 Hz, 1H), 7.79-7.70 (m, 2H),7.58 (d, J=7.8 Hz, 2H), 5.64-5.54 (m, 1H), 5.06 (d, J=15.6 Hz, 1H), 4.79(dd, J=16.1, 2.0 Hz, 1H), 4.44 (d, J=15.6 Hz, 1H), 4.28-4.15 (m, 2H),3.88-3.80 (m, 2H). Analytical chiral HPLC RT: 1.72 min (CHIRALPAK IG-3;0.46 cm×5 cm; 3 micro; Hex (0.1% DEA):EtOH=50:50 at 1 ml/min).

Enantiomer 857B: LCMS (ES) m/z 432 (M+H). ¹H NMR (300 MHz, DMSO-d₆) δ8.48 (d, J=2.1 Hz, 1H), 8.24 (dd, J=9.5, 2.2 Hz, 1H), 7.75 (d, J=8.1 Hz,2H), 7.58 (d, J=8.0 Hz, 2H), 5.59 (t, J=4.8 Hz, 1H), 5.06 (d, J=15.6 Hz,1H), 4.79 (d, J=16.2 Hz, 1H), 4.44 (d, J=15.6 Hz, 1H), 4.27-4.15 (m,2H), 3.83 (dd, J=5.0, 2.4 Hz, 2H. Analytical chiral HPLC RT: 2.61 min(CHIRALPAK IG-3; 0.46 cm×5 cm; 3 micro; Hex (0.1% DEA):EtOH=50:50 at 1ml/min).

The following compounds were prepared by methods analogous to the methoddescribed for Enantiomers 857A and 857B:

Enantiomer LRMS (ES) Retention HPLC No. m/z Time (min) SeparationConditions 862A M + H = 398 1.34 CHIRALPAK ID-3; 0.46 cm × 5 cm; 862BM + H = 398 1.83 3 micro; Hex(0.1% DEA):EtOH = 50:50 at 1 ml/min

Example 61: Synthesis of Compound 859 1. Synthesis of Intermediate 61-1

To a solution of (4-(trifluoromethyl)phenyl)methanamine (2.76 g, 15.73mmol, 1.1 equiv) in 2,2,2-trifluoroethanol (10.0 mL) was added ethyl3-oxocyclobutane-1-carboxylate (2.03 g, 14.30 mmol, 1.0 equiv). Afterstirring at r.t. for 10 min, to this resulting mixture were added5-chloro-3-fluoro-2-isocyanopyridine (2.53 g, 14.30 mmol, 1.0 equiv) andchloroacetic acid (1.49 g, 15.73 mmol, 1.1 equiv). The resulting mixturewas stirred at r.t. for 3 h, concentrated under reduced pressure, andpurified silica gel chromatography, eluted with EA/HE to afford 1.6 g(20%) of ethyl3-((5-chloro-3-fluoropyridin-2-yl)carbamoyl)-3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxylate(Intermediate 61-1) as a foam. LRMS (ES) m/z 550 (M+H). ¹H NMR (400 MHz,Methylene Chloride-d₂) δ 9.55 (s, OH), 9.36 (s, 1H), 8.15 (dd, J=4.5,2.1 Hz, 1H), 7.57 (dd, J=17.6, 8.1 Hz, 2H), 7.46 (dd, J=9.2, 2.1 Hz,1H), 7.34 (t, J=6.6 Hz, 2H), 4.57 (s, 2H), 4.09-3.97 (m, 2H), 3.90 (d,J=10.6 Hz, 2H), 3.07-2.97 (m, 3H), 2.83 (p, J=8.9 Hz, 1H), 2.74-2.61 (m,1H), 2.52 (dd, J=12.3, 9.6 Hz, 1H), 1.12 (q, J=6.9 Hz, 3H).

2. Synthesis of Compound 859 (mixture of Diastereomers 859A and 859B

To a solution of ethyl3-((5-chloro-3-fluoropyridin-2-yl)carbamoyl)-3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxylate(1.5 g, 2.73 mmol, 1.0 equiv) in DMF (10.0 mL) at r.t was added K₂CO₃(1.14 g, 8.18 mmol, 3.0 equiv). The mixture was stirred at 80° C. for 1h, diluted with EA (20 mL), filtered, and concentrated. The residue waspurified on silica gel column with EA/HE as eluent to afford thecorresponding Diastereomers 859A (680 mg, 49%) and 859B (610 mg, 44%) ofethyl8-(5-chloro-3-fluoropyridin-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane-2-carboxylate(i.e., the (2r,4r) and (2s,4s) diastereomers).

Characterization of Diastereomer 859A: LRMS (ES) m/z 514 (M+H). ¹H NMR(400 MHz, Methylene Chloride-d₂) δ 8.23 (d, J=2.1 Hz, 1H), 7.58-7.50 (m,3H), 7.30 (d, J=8.0 Hz, 2H), 4.95 (s, 2H), 4.43 (s, 2H), 4.01 (q, J=7.1Hz, 2H), 3.01 (p, J=8.8 Hz, 1H), 2.83-2.72 (m, 2H), 2.63 (dd, J=12.9,9.4 Hz, 2H), 1.12 (t, J=7.1 Hz, 3H).

Characterization of Diastereomer 859B: LRMS (ES) m/z 514 (M+H). ¹H NMR(400 MHz, Methylene Chloride-d₂) δ 8.22 (s, 1H), 7.58-7.49 (m, 3H), 7.29(d, J=8.0 Hz, 2H), 4.91 (s, 2H), 4.41 (s, 2H), 4.00 (q, J=7.1 Hz, 2H),3.11-3.01 (m, 2H), 3.01-2.87 (m, 1H), 2.64-2.53 (m, 2H), 1.10 (t, J=7.1Hz, 3H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 859:

LRMS (ES) Compound No. m/z ¹H NMR 860A M + H = 480 (400 MHz, MethyleneChloride-d₂) δ 8.23 (d, J = 2.1 Hz, 1H), 7.54 (dd, J = 8.9, 2.1 Hz, 1H),7.28-7.18 (m, 2H), 7.12 (d, J = 8.3 Hz, 2H), 4.85 (s, 2H), 4.41 (s, 2H),4.02 (q, J = 7.1 Hz, 2H), 3.07-2.93 (m, 1H), 2.81-2.71 (m, 2H),2.69-2.59 (m, 2H), 1.13 (t, J = 7.1 Hz, 3H) 860B M + H = 480 (400 MHz,Methylene Chloride-d2) δ 8.34 (d, J = 2.1 Hz, 1H), 7.65 (dd, J = 8.9,2.1 Hz, 1H), 7.38 (d, J-8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 4.94 (s,2H), 4.52 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.22-3.12 (m, 2H),3.10-2.96 (m, 1H), 2.77-2.66 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H)

Example 62: Synthesis of Compound 861 1. Synthesis of Intermediate 62-1

To a solution of 1-[4-(trifluoromethyl)phenyl]methanamine (15.3 g, 87.1mmol, 1.1 equiv) in trifluoroethanol (40.0 mL) was addedoxetane-3-carbaldehyde (7.5 g, 87.1 mmol, 1.1 equiv). After stirring atr.t. for 10 min, to the mixture was added5-chloro-3-fluoro-2-isocyanopyridine (12.4 g, 79.2 mmol, 1.0 equiv) andchloroacetic acid (8.2 g, 87.1 mmol, 1.1 equiv). The resulting mixturewas stirred at r.t. for overnight, concentrated under reduced pressure,and purified by silica gel column chromatography, eluted with PE/EtOAc(2/1) to afford 33.5 g of2-chloro-N-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-(oxetan-3-yl)-2-oxoethyl)-N-(4-(trifluoromethyl)benzyl)acetamide(Intermediate 62-1) as a yellow oil. LRMS (ES) m/z 494 (M+H).

2. Synthesis of Compound 861

To a solution of2-chloro-N-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-(oxetan-3-yl)-2-oxoethyl)-N-(4-(trifluoromethyl)benzyl)acetamide(33.5 g, 67.8 mmol, 1.0 equiv) in DMF (350.0 mL) was added potassiumcarbonate (18.9 g, 135.6 mmol, 2.0 equiv). To the resulting mixturestirred at r.t. for 30 min was added water (800 mL). The precipitateswere collected by filtration, washed with water (400 mL) twice, anddried under high vacuum to afford 26 g of1-(5-chloro-3-fluoropyridin-2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Compound 861) as an off-white solid. LRMS (ES) m/z 458 (M+H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 861:

Compound No. LRMS (ES) m/z 612 M + H = 508 633 M + H = 424 636 M + H =432 639 M + H = 472 640 M + H = 438 645 M + H = 454.0 646 M + H = 408647 M + H = 426 648 M + H = 442 649 M + H = 476 650 M + H = 440 651 M +H = 468 654 M + H = 420 655 M + H = 434 656 M + H = 487 657 M + H = 466661 M + H = 513 662 M + H = 479 664 M + H = 422.0 666 M + H = 404.0 667M + H = 422.0 668 M + H = 442.0 700 M + H = 451 706 M + H = 398.0 707M + H = 452.0 708 M + H = 468.0 714 M + H = 404 717 M + H = 438 720 M +H = 422 724 M + H = 418 727 M + H = 418 730 M + H = 438 733 M + H = 400

3. Separation of Compound 861 Enantiomers: Enantiomers 861A and 861B

The racemic compound of1-(5-chloro-3-fluoropyridin-2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(26 g, 57 mmol, 1.0 equiv) was separated by Prep-SFC with the followingconditions (Prep SFC80-1): Column, CHIRALPAK IC, 3*25 cm, 5 um; mobilephase, CO₂ (65%) and EtOH-(35%); Detector, UV254 nm) to afford 11.4 g(first eluted peak) of Enantiomer 861A and 11.2 g (second eluted peak)of Enantiomers 861B as white solids.

Characterization of Enantiomer 861A. LCMS (ES) m/z 458 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 8.48 (d, J=2.1 Hz, 1H), 8.24 (dd, J=9.5, 2.1 Hz,1H), 7.72 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 4.84 (dd, J=16.4,11.0 Hz, 2H), 4.71-4.51 (m, 3H), 4.54-4.38 (m, 2H), 4.37 (d, J=16.9 Hz,1H), 4.25 (dd, J=7.9, 6.0 Hz, 1H), 3.76 (h, J=7.7 Hz, 1H). Analyticalchiral HPLC RT: 0.51 min (CHIRALPAK IC-U; 0.3 cm×5 cm; 1.6 micro; MtBE(0.1% DEA):EtOH=60:40 at 0.7 ml/min).

Characterization of Enantiomer 861B. LCMS (ES) m/z 458 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 8.48 (d, J=2.1 Hz, 1H), 8.24 (dd, J=9.4, 2.2 Hz,1H), 7.72 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 4.84 (dd, J=16.4,11.1 Hz, 2H), 4.71-4.51 (m, 3H), 4.54-4.38 (m, 2H), 4.38 (d, J=16.9 Hz,1H), 4.25 (dd, J=7.9, 6.0 Hz, 1H), 3.76 (h, J=7.8 Hz, 1H). Analyticalchiral HPLC RT: 0.64 min (CHIRALPAK IC-U; 0.3 cm×5 cm; 1.6 micro; MtBE(0.1% DEA):EtOH=60:40 at 0.7 ml/min).

The following compounds were prepared by methods analogous to the methoddescribed for Enantiomers 861A and 861B:

HPLC Separation Conditions Letter HPLC Conditions I CHIRALPAK IE-3; 0.46cm × 5 cm; 3 micro; Hex(0.1% DEA):EtOH = 50:50 at 1 ml/min J CHIRALPAKID-3; 0.46 cm × 5 cm; 3 micro; Hex(0.1% DEA):EtOH = 50:50 at 1 ml/min KCHIRALPAK IA-U; 0.3 cm × 5 cm; 1.6 micro; MtBE(0.1% DEA):EtOH = 50:50 at0.7 ml/min L CHIRALPAK IE-3; 0.46 cm × 5 cm; 3 micro; MtBE(0.1%DEA):MeOH = 50:50 at 1 ml/min M CHIRALPAK IG-3; 0.46 cm × 5 cm; 3 micro;MtBE(0.1% DEA):EtOH = 50:50 at 1 ml/min N CHIRALPAK IC-3; 0.46 cm × 5cm; 3 micro; (Hex:DCM = 3:1)(0.1% DEA):EtOH = 50:50 at 1 ml/min OCHIRALPAK IC-3; 0.46 cm × 5 cm; 3 micro; (Hex:DCM = 3:1)(0.1% DEA):EtOH= 50:50 at 2 ml/min P CHIRALPAK IC-3; 0.46 cm × 5 cm; 3 micro; (Hex:DCM= 1:1)(0.1% DEA):EtOH = 50:50 at 1 ml/min Q CHIRALPAK IE-3; 0.46 cm × 5cm; 3 micro; MtBE(0.1% DEA):EtOH = 50:50 at 1 ml/min R CHIRALPAK ID-3;0.46 cm × 5 cm; 3 micro; MtBE(0.1% DEA):MeOH = 50:50 at 1 ml/min SCHIRAL Cellulose-SB; 0.46 cm × 10 cm; 3 micro; MtBE(0.1% DEA):EtOH =70:30 at 1 ml/min T CHIRALPAK IE-3; 0.46 cm × 5 cm; 3 micro; (Hex:DCM =3:1)(0.1% DEA):EtOH = 50:50 at 1 ml/min X CHIRALPAK ID-3; 0.46 cm × 5cm; 3 micro; MtBE(0.1% DEA):EtOH = 50:50 at 1 ml/min HPLC LRMS RetentionSeparation Compound No. (ES) m/z Time (min) Conditions 863A M + H = 4101.982 I 863B M + H = 410 2.875 I 573A M + H = 446 1.196 J 573B M + H =446 1.640 J 864A M + H = 458 1.111 J 864B M + H = 458 2.081 J 612A M + H= 508 0.899 K 612B M + H = 508 1.179 K 633A M + H = 424 1.038 L 633B M +H = 424 1.94 L 636A M + H = 432 0.97 M 636B M + H = 432 1.33 M 657A M +H = 466 1.29 I 657B M + H = 466 2.30 I 650A M + H = 440 2.17 N 650B M +H = 440 3.16 N 654A M + H = 420 2.18 N 654B M + H = 420 2.90 N 639A M +H = 472 1.77 N 639B M + H = 472 3.10 N 640A M + H = 438 1.34 O 640B M +H = 438 2.02 O 643A M + H = 499 1.38 O 644A M + H = 465 2.28 P 649A M +H = 476 1.55 N 649B M + H = 476 2.86 N 647A M + H = 426 1.47 P 647B M +H = 426 2.55 P 646A M + H = 408 2.24 N 646B M + H = 408 3.46 N 648A M +H = 442 1.52 P 648B M + H = 442 2.64 P 645A M + H = 454 1.01 Q 664A M +H = 422 2.61 N 664B M + H = 422 3.91 N 667A M + H = 422 2.21 N 667B M +H = 422 2.93 N 668A M + H = 442 2.07 N 668B M + H = 442 3.30 N 714A M +H = 404 1.10 R 714B M + H = 404 3.07 R 717A M + H = 438 2.87 S 717B M +H = 438 3.27 S 720A M + H = 422 1.02 R 720B M + H = 422 2.76 R 724A M +H = 418 1.46 X 724B M + H = 418 3.89 X 727B M + H = 418 1.78 T 727A M +H = 418 2.58 T 730A M + H = 438 1.14 Q 730B M + H = 438 2.15 Q 730A M +H = 400 1.31 Q 730B M + H = 400 2.54 Q

Compound LRMS Retention No. (ES) m/z Time (min) SFC Conditions 666A M +H = 404 1.39 CHIRALPAK AS-3; 0.3 cm × 10 cm; 3 666B M + H = 404 1.83micro; Gradient A: CO2; Gradient (B %): MeOH(0.1% DEA); Gradient (B %):5% to 20% in 2 min, hold 1 min at 20%; at 2 ml/min

Compound LRMS No. (ES) m/z ¹H NMR 865A M + H = 446 (300 MHz, DMSO-d₆) δ8.50 (d, J = 2.1 Hz 1H), 8.26 (dd, J = 9.0, 2.4 Hz, 1H), 7.73 (d, J =8.2 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 5.52 (t, J = 4.6, Hz, 1H), 5.04(d, J = 15.6 Hz, 1H), 4.64 (q, J = 6.9 Hz, 1H), 4.41 (d,J = 15.9 Hz,1H), 4.11 (s, 1H), 3.90-3.75 (m, 2 H), 1.53 (d, J = 6.9 Hz, 3H) 888A M +H = 446 (300 MHz, DMSO-d₆) δ 8.52 (s, 1H), 8.50 (d, J = 2.1 Hz 1H), 8.25(dd, J = 9.3, 2.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1Hz, 2H), 5.52 (br, 1H), 5.13 (d, J = 15.9 Hz, 1H), 4.85 (q, J = 7 Hz,1H), 4.42 (d,J = 15.9 Hz, 1H), 4.21 (s, 1H), 3.92-3.73 (m, 2 H), 1.18(d, J = 7 Hz, 3H)

The following compounds were prepared by methods analogous to the methoddescribed for Enantiomers 861A and 861B and using racemic2-((tert-butyldimethylsilyl)oxy)propanal instead ofoxetane-3-carbaldehyde:

Compound No. LRMS (ES) m/z ¹H NMR 858A M + H = 446 (400 MHz, MethyleneChloride-d₂) δ 8.21 (d, J = 2.1 Hz, 1H), 7.58-7.47 (m, 3H), 7.33 (d, J =8.0 Hz, 2H), 5.37 (d, J = 15.5 Hz, 1H), 4.72 (dd, J = 16.7, 4.1 Hz, 1H),4.29-4.19 (m, 2H), 4.16 (d, J = 15.5 Hz, 1H), 3.91 (d, J = 4.1 Hz, 1H),2.57 (s, 1H), 1.27 (dd, J = 6.5, 4.1 Hz, 3H) 858B M + H = 446 (400 MHz,Methylene Chloride-d₂) δ 8.19 (d, J = 2.1 Hz, 1H), 7.57-7.46 (m, 3H),7.35 (d, J = 8.0 Hz, 2H), 5.19 (s, 1H), 4.72 (d, J = 16.6 Hz, 1H),4.28-4.13 (m, 3H), 3.79 (d, J = 2.4 Hz, 1H), 3.00 (s, 1H), 1.24 (d, J =6.6 Hz, 3H)

The following compounds were prepared by methods analogous to the methoddescribed for Enantiomers 861A and 861B and using(S)-2-((tert-butyldimethylsilyl)oxy)propanal instead ofoxetane-3-carbaldehyde:

Compound No. LRMS (ES) m/z ¹H NMR 858C M + H = 446 (400 MHz, MethyleneChloride-d₂) δ 8.21 (d, J = 2.1 Hz, 1H), 7.58-7.47 (m, 3H), 7.35 (dd, J= 13.0, 8.0 Hz, 2H), 5.18 (d, J = 15.5 Hz, 1H), 4.72 (dd, J = 16.7, 3.2Hz, 1H), 4.24 (dd, J = 16.0, 6.2 Hz, 2H), 4.22-4.12 (m, 1H), 3.81 (d, J= 2.4 Hz, 1H), 2.28 (s, 1H), 1.27 (d, J = 6.5 Hz, 3H). 858D M + H = 446(400 MHz, Methylene Chloride-d₂) δ 8.21 (d, J = 2.0 Hz, 1H), 7.58-7.48(m, 3H), 7.33 (d,J = 8.0 Hz, 2H), 5.37 (d, J = 15.5 Hz, 1H), 4.71 (d, J= 16.8 Hz, 1H), 4.28-4.16 (m, 2H), 4.15 (d,J = 15.5 Hz, 1H), 3.90 (d, J= 4.1 Hz, 1H), 2.76 (s, 1H), 1.27 (d, J = 6.5 Hz, 3H).

Example 63: Synthesis of tert-butyl3-((5-chloro-3-fluoropyridin-2-yl)carbamoyl)-3-(2-chloro-N-(4-(difluoromethyl)benzyl)acetamido)cyclobutane-1-carboxylate(mixture of Intermediate Diastereomers 71-1A and 71-1B

To a solution of (4-(difluoromethyl)phenyl)methanamine (1.0 g, 6.3 mmol,1.0 equiv) in 2,2,2-trifluoroethanol (5.0 mL) was added tert-butyl3-oxocyclobutane-1-carboxylate (1.1 g, 6.3 mmol, 1.0 equiv). Afterstirring at r.t. for 10 min, to this resulting mixture were added5-chloro-3-fluoro-2-isocyanopyridine (1.0 g, 6.3 mmol, 1.0 equiv) andchloroacetic acid (0.66 g, 7.0 mmol, 1.1 equiv). The resulting mixturewas stirred at r.t. overnight, concentrated under reduced pressure, andpurified silica gel chromatography, eluted with EA/HE to afford 800 mg(22%) of Intermediate Diastereomer 71-1A (first peak, less polar) and1.0 g (28%) of Intermediate Diastereomer 71-1B (second peak, morepolar). LRMS (ES) m/z 560 (M+H) for both isomers.

Example 64: Synthesis of Compound 630 1. Synthesis of Intermediate 64-1

To a solution of 1-bromopropan-2-one (5 g, 36.5 mmol, 1.0 equiv) in ACN(50 mL) was added potassium 1,3-dioxoisoindolin-2-ide (7.5 g, 40.5 mmol,1.11 equiv.). The mixture was stirred at 80° C. for 2 h, cooled to rt,and quenched with water (50 mL), and extracted with DCM (50 mL) twice.The combined organic layer was washed with brine (100 mL), dried overNa₂SO₄, concentrated under reduced pressure, and purified by silica gelcolumn chromatography using PE/EA (1/2) as eluent to afford 6.6 g of2-(2-oxopropyl)isoindoline-1,3-dione (Intermediate 64-1) as a yellowsolid. LRMS (ES) m/z 204 (M+H).

2. Synthesis of Intermediate 64-2

To a solution of 1-[4-(trifluoromethyl)phenyl]methanamine (1.7 g, 9.7mmol, 1.5 equiv) in trifluoroethanol (10.0 mL) was added2-(2-oxopropyl)isoindoline-1,3-dione (2.0 g, 9.6 mmol, 1.5 equiv). Afterstirring at r.t. for 10 min, to the mixture was added5-chloro-3-fluoro-2-isocyanopyridine (1.0 g, 6.4 mmol, 1.0 equiv) andchloroacetic acid (899.4 mg, 9.5 mmol, 1.5 equiv). The resulting mixturewas stirred at 60° C. overnight, concentrated under vacuum, and purifiedby C18 column, eluted with water (0.5% NH₄HCO₃)/ACN (1/5) to afford 750mg ofN-(5-chloro-3-fluoropyridin-2-yl)-2-(2-chloro-N-[[4-(trifluoromethyl)phenyl]methyl]acetamido)-3-(1,3-dioxoisoindol-2-yl)-2-methylpropanamide(Intermediate 64-2) as a yellow oil. LRMS (ES) m/z 611 (M+H).

3. Synthesis of Intermediate 64-3

To a solution ofN-(5-chloro-3-fluoropyridin-2-yl)-2-(2-chloro-N-[[4-(trifluoromethyl)phenyl]methyl]acetamido)-3-(1,3-dioxoisoindol-2-yl)-2-methylpropanamide(700.0 mg, 1.1 mmol, 1.0 equiv) in dimethylformamide (7.0 mL) was addedpotassium carbonate (317.0 mg, 2.3 mmol, 2.0 equiv). The resultingmixture was stirred at 60° C. for 30 min, cooled to r.t., and dilutedwith water (15 mL). The precipitates were collected by filtration,washed with water (10 mL) twice, dried, and purified by silica gelcolumn chromatography, eluted with PE/EtOAc (4:/) to afford 400 mg of2-((4-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)methyl)isoindoline-1,3-dione(Intermediate 64-3) as an off-white solid. LRMS (ES) m/z 575 (M+H).

4. Synthesis of Intermediate 64-4

To a solution of2-((4-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)methyl)isoindoline-1,3-dione(320.0 mg, 0.56 mmol, 1.0 equiv) in EtOH (5.0 mL) was added NH₂NH₂.H₂O(83.0 mg, 1.7 mmol, 3.0 equiv). The resulting mixture was stirred at 80°C. for 2 h, cooled to r.t, filtered to remove solids, and concentratedunder reduced pressure to afford 200 mg of3-(aminomethyl)-1-(5-chloro-3-fluoropyridin-2-yl)-3-methyl-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Intermediate 64-4) as a yellow oil. LRMS (ES) m/z 445 (M+H).

5. Synthesis of Compound 630

To a solution of3-(aminomethyl)-1-(5-chloro-3-fluoropyridin-2-yl)-3-methyl-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(200 mg, 0.45 mmol, 1.0 equiv) in DCM (2 mL) were added acetic anhydride(55 mg, 0.54 mmol, 1.2 equiv.) and TEA (91 mg, 0.9 mmol, 2.0 equiv.).The mixture was stirred at rt for 2 h, concentrated under reducedpressure, and purified Prep-HPLC with the following conditions:(SHIMADZU (HPLC-01)): Column, XBridge Prep OBD C18 Column, 30*150 mm 5um; mobile phase, Water (10 mM NH₄HCO₃+0.1% NH₃.H₂O) and ACN (38%gradient up to 60% in 9 min); Detector UV 254 nm) to afford 140 mg ofN-((4-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)methyl)acetamide(Compound 630) as a white solid. LCMS (ES) m/z 487 (M+H). ¹H NMR (300MHz, Methanol-d₄) δ 8.42 (d, J=1.9 Hz, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.66(d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 5.29 (d, J=16.7 Hz, 1H),4.83-4.75 (m, 1H), 4.58-4.44 (m, 2H), 3.96 (d, J=14.0 Hz, 1H), 3.53 (d,J=14.4 Hz, 1H), 1.96 (d, J=1.5 Hz, 3H), 1.58-1.51 (m, 3H).

The following compound was prepared by methods analogous to the methoddescribed for Compound 861:

Compound No. LRMS (ES) m/z 631 M + H = 453

6. Separation of Compound 630 Enantiomers: Enantiomers 630A and 630B

The racemic compound ofN-((4-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)methyl)acetamide(90 mg, 0.19 mmol, 1.0 equiv) was purified by Chiral-Prep-HPLC with thefollowing conditions ((Prep-HPLC-009): Column, CHIRALPAK IE, 2*25 cm, 5um; mobile phase, 30% EtOH in Hex (8 mM NH₃.MeOH) for 15 min; Detector,UV254 nm) to afford 37 mg of (first eluted peak) Enantiomer 630A and 39mg of (second eluted peak) Enantiomer 630B as white solids.

Characterization of Enantiomer 630A. LCMS (ES) m/z 487 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 8.51 (d, J=2.1 Hz, 1H), 8.29-8.20 (m, 2H), 7.70 (d,J=8.1 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 5.07 (d, J=16.9 Hz, 1H), 4.64 (d,J=17.0 Hz, 1H), 4.46 (t, J=17.5 Hz, 2H), 3.81 (dd, J=14.1, 7.1 Hz, 1H),3.37 (dd, J=14.1, 5.4 Hz, 1H), 1.82 (s, 3H), 1.43 (s, 3H). Analyticalchiral HPLC RT: 2.33 min (CHIRALPAK IE-3; 0.46 cm×5 cm; 3 micro; Hex(0.1% DEA):EtOH=70:30 at 1 ml/min).

Characterization of Enantiomer 630B. LCMS (ES) m/z 487 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 8.51 (d, J=2.1 Hz, 1H), 8.30-8.20 (m, 2H), 7.70 (d,J=8.1 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 5.07 (d, J=16.9 Hz, 1H), 4.64 (d,J=17.0 Hz, 1H), 4.46 (t, J=17.5 Hz, 2H), 3.81 (dd, J=14.1, 7.1 Hz, 1H),3.44-3.33 (m, 1H), 1.82 (s, 3H), 1.43 (s, 3H). Analytical chiral HPLCRT: 2.71 min (CHIRALPAK IE-3; 0.46 cm×5 cm; 3 micro; Hex (0.1%DEA):EtOH=70:30 at 1 ml/min).

Example 65: Synthesis of Compound 691 1. Synthesis of Intermediate 65-1

To a solution of methyl 2-amino-2-(oxetan-3-yl)acetate (3.0 g, 20.7mmol, 1.0 equiv) in DCE (60.0 mL) was added4-(trifluoromethyl)benzaldehyde (3.6 g, 21 mmol, 1.0 equiv). Afterstirring at r.t. for 30 min, to the mixture was added AcOH (2.50 g,41.631 mmol, 2.01 equiv) and STAB (8.80 g, 41.521 mmol, 2.01 equiv) atroom temperature. The resulting mixture was stirred at r.t. overnight,adjust the pH to 8 with ammonium hydroxide (200 mL), and extracted withDCM (300 mL) twice. The combined organic layers were washed with brine(200 mL) twice, dried over anhydrous Na₂SO₄, concentrated under reducedpressure, and purified by C18 column, eluted with water (0.5%NH₄HCO₃)/ACN (1:1) to afford 5.2 g of methyl2-(oxetan-3-yl)-2-((4-(trifluoromethyl)benzyl)amino)acetate(Intermediate 65-1) as a yellow solid. LRMS (ES) m/z 304 (M+H).

2. Synthesis of Intermediate 65-2

To a solution of methyl2-(oxetan-3-yl)-2-((4-(trifluoromethyl)benzyl)amino)acetate (5.0 g, 16.5mmol, 1.0 equiv) in DCM (100 mL) at 0° C. were added K₂CO₃ (0.5 M, 49mL, 24.6 mmol, 1.5 equiv) and bromoacetyl bromide (4.0 g, 19.8 mmol, 1.2equiv). The resulting mixture was stirred at r.t. for 2 h and extractedwith DCM (50 mL) twice. The combined organic layers were washed withbrine (100 mL) twice, dried over anhydrous Na₂SO₄, and concentratedunder reduced pressure to afford 7.1 g of methyl2-(2-bromo-N-[[4-(trifluoromethyl)phenyl]methyl]acetamido)-2-(oxetan-3-yl)acetate(Intermediate 65-2) as a yellow oil. LRMS (ES) m/z 424 (M+H).

3. Synthesis of Intermediate 65-3

To methyl2-(2-bromo-N-[[4-(trifluoromethyl)phenyl]methyl]acetamido)-2-(oxetan-3-yl)acetate(7.0 g, 16.5 mmol, 1.0 equiv) in RB flask was added NH₃ in MeOH (70.0mL, 7M). The mixture was stirred at r.t. overnight, concentrated undervacuum, and triturated with ethyl acetate (100 mL) to afford 5.7 g of6-(oxetan-3-yl)-1-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Intermediate 65-3) as an off-white solid. LRMS (ES) m/z 329 (M+H).

4. Synthesis of Compound 691

To a solution of6-(oxetan-3-yl)-1-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione (120.0mg, 0.37 mmol, 1.0 equiv) in dioxane (4 mL) at r.t. were added(2-aminoethyl)dimethylamine (18.0 mg, 0.21 mmol, 0.56 equiv),2-bromo-3-fluoro-5-methylpyridine (102.1 mg, 0.54 mmol, 1.5 equiv), CuI(36.2 mg, 0.19 mmol, 0.5 equiv), and K₂CO₃ (150.0 mg, 1.1 mmol, 3.0equiv.). The resulting mixture was stirred at 115° C. for 2 h undernitrogen, cooled to r.t., diluted with water (10 mL), and extracted withEtOAc (10 mL) twice. The combined organic layers were washed with brine(10 mL) twice, dried over anhydrous Na₂SO₄, concentrated under reducedpressure, and purified by Prep-HPLC with the following conditions(SHIMADZU (HPLC-01)): Column, XBridge Shield RP18 OBD Column, 5 um,19*150 mm; mobile phase, Water (0.05% TFA) and ACN (43% gradient up to45% in 9 min); Detector, UV254 nm) to afford 100 mg of1-(3-fluoro-5-methylpyridin-2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Compound 691) as a yellow oil. LRMS (ES) m/z 438 (M+H). 1H NMR (300MHz, Methanol-d₄) δ 8.21 (s, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.60 (d,J=10.5 Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 5.00 (d, J=16.1 Hz, 1H),4.842-4.897 (m, 1H), 4.76 (d, J=17.4 Hz, 1H), 4.68-4.55 (m, 3H),4.55-4.39 (m, 3H), 3.78 (dt, J=17.4, 8.4 Hz, 1H), 2.42 (d, J=0.8 Hz,3H).

5. Separation of Compound 691 Enantiomers: Enantiomers 691A and 691B

The racemic compound of1-(3-fluoro-5-methylpyridin-2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(80 mg, 0.18 mmol, 1.0 equiv) was purified by Chiral-Prep-HPLC with thefollowing conditions ((Prep-HPLC-009): Column, CHIRALPAK IE, 2*25 cm, 5um; mobile phase, 40% EtOH in MTBE (8 mM NH₃.MeOH) for 19 min; Detector,UV 254 nm) to afford 25 mg of (first eluted peak) Enantiomer 691A and 17mg of (second eluted peak) Enantiomer 691B as white solids.

Characterization of Enantiomer 691A. LCMS (ES) m/z 438 (M+H). ¹H NMR(300 MHz, Methanol-d₄) δ 8.21 (s, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.60 (d,J=10.4 Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 5.00 (d, J=15.9 Hz, 1H),4.84-4.89 (m, 1H), 4.76 (d, J=17.4 Hz, 1H), 4.68-4.56 (m, 3H), 4.56-4.40(m, 3H), 3.86-3.72 (m, 1H), 2.42 (s, 3H). Analytical chiral HPLC RT:1.16 min (CHIRALPAK IE-3; 0.46 cm×5 cm; 3 micro; MtBE (0.1%DEA):EtOH=50:50 at 1 ml/min).

Characterization of Enantiomer 691B. LCMS (ES) m/z 438 (M+H). ¹H NMR(300 MHz, Methanol-d₄) δ 8.21 (s, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.60 (d,J=10.4 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 5.00 (d, J=15.9 Hz, 1H),4.84-4.89 (m, 1H), 4.76 (d, J=17.4 Hz, 1H), 4.68-4.55 (m, 3H), 4.55-4.40(m, 3H), 3.86-3.72 (m, 1H), 2.42 (s, 3H). Analytical chiral HPLC RT:2.76 min (CHIRALPAK IE-3; 0.46 cm×5 cm; 3 micro; MtBE (0.1%DEA):EtOH=50:50 at 1 ml/min).

Example 66: Synthesis of Compound 701 1. Synthesis of Intermediate 66-1

To a suspension of compound 202 (3.0 g, 6.3 mmol, 1.0 equiv) in ethanol(20.0 mL) was added hydroxyl amine (2.0 mL, 50% wt in water). Afterstirring at r.t. overnight, the precipitate was collected by filtration,washed with additional water, and dried to give 1.6 g (50%) of4-(2-acetyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluoro-N-hydroxybenzimidamide(Intermediate 66-1) as a white solid. LRMS (ES) m/z 508 (M+H). ¹H NMR(400 MHz, DMSO-d₆) δ 9.87 (d, J=1.6 Hz, 1H), 7.78-7.71 (m, 2H), 7.60(dt, J=19.1, 8.2 Hz, 5H), 5.97 (s, 2H), 5.03 (s, 2H), 4.56 (d, J=9.9 Hz,1H), 4.49 (s, 2H), 4.38 (d, J=9.7 Hz, 1H), 4.28 (d, J=10.5 Hz, 1H), 4.04(d, J=10.5 Hz, 1H), 1.75 (s, 3H).

2. Synthesis of Compound 701

To a solution of4-(2-acetyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluoro-N-hydroxybenzimidamide(100 mg, 0.2 mmol, 1.0 equiv) in trimethoxymethane (1.0 mL) at r.t wasadded PTSA (3.39 mg, 0.02 mmol, 0.1 equiv). The mixture was stirred atreflux overnight, cooled to r.t., concentrated to dryness, andtriturated with ACN (5.0 mL). The solid was collected and dried toafford 81 mg (79%) of2-acetyl-8-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl)-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione(Compound 701). LRMS (ES) m/z 518.1 (M+H). ¹H NMR (400 MHz, MethyleneChloride-d₂) δ 8.90 (d, J=1.7 Hz, 1H), 8.07 (dd, J=16.1, 9.6 Hz, 2H),7.71 (d, J=7.9 Hz, 2H), 7.60-7.51 (m, 1H), 7.47 (d, J=8.0 Hz, 2H), 5.21(d, J=16.5 Hz, 1H), 5.00 (d, J=16.4 Hz, 1H), 4.77 (d, J=9.3 Hz, 1H),4.61 (d, J=10.6 Hz, 1H), 4.51 (s, 2H), 4.27 (dd, J=20.0, 9.9 Hz, 2H),1.86 (d, J=1.7 Hz, 3H).

The following compound was prepared by methods analogous to the methoddescribed for Compound 701:

Compound No. LRMS (ES) m/z 702 M + H = 532.0

Example 67: Synthesis of Compound 703 1. Synthesis of Intermediate 67-1

To a solution of 6-chloro-5-fluoropyridin-3-ol (500.0 mg, 3.4 mmol, 1.0equiv) in acetone (5.0 mL) at r.t. were added K₂CO₃ (697.9 mg, 5.1 mmol,1.5 equiv) and iodomethane (524.4 mg, 3.7 mmol, 1.1 equiv). Theresulting mixture was stirred at 60° C. for 2 h, cooled to r.t., dilutedwith water (20 mL), and extracted with EtOAc (30 mL) twice. The combinedorganic layers were washed with brine (30 mL) twice, dried overanhydrous Na₂SO₄, and concentrated under reduced pressure to afford 500mg of 2-chloro-3-fluoro-5-methoxypyridine (Intermediate 67-1) as ayellow oil. LRMS (ES) m/z 162 (M+H).

2. Synthesis of Compound 703

To a solution of6-(oxetan-3-yl)-1-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione (150.0mg, 0.46 mmol, 1.0 equiv) in dioxane (1.0 mL) at r.t. were addedcopper(I) iodide (45.3 mg, 0.24 mmol, 0.5 equiv),2-chloro-3-fluoro-5-methoxypyridine (112.2 mg, 0.7 mmol, 1.5 equiv),(2-aminoethyl)dimethylamine (22.6 mg, 0.26 mmol, 0.56 equiv), and K₂CO₃(187.6 mg, 1.36 mmol, 3.0 equiv). The resulting mixture was stirred at110° C. for 2 h, cooled to r.t., filtered off the solids, diluted withwater (10 mL), and extracted with EA (10 ml) twice. The combined organiclayers were washed with brine (10 mL) twice, dried over anhydrousNa₂SO₄, concentrated under reduced pressure, and purified by Prep-HPLCwith the following conditions ((SHIMADZU (HPLC-01)): Column, XBridgePrep OBD C18 Column, 30*150 mm 5 um; mobile phase, Water (0.05% TFA) andACN (40% gradient up to 48% in 9 min); Detector, UV254 nm) to afford 100mg of1-(3-fluoro-5-methoxypyridin-2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Compound 703) as a white solid. LRMS (ES) m/z 454 (M+H). 1H NMR (300MHz, Methanol-d₄) δ 8.08 (d, J=2.6 Hz, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.52(d, J=8.1 Hz, 2H), 7.42 (dd, J=10.9, 2.6 Hz, 1H), 5.00 (d, J=15.8 Hz,1H), 4.83-4.69 (m, 2H), 4.69-4.35 (m, 6H), 3.93 (s, 3H), 3.86-3.69 (m,1H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 703:

Compound No. LRMS (ES) m/z 691 M + H = 438 711 M + H = 490 723 M + H =416.1 736 M + H = 449 747 M + H = 457 758 M + H = 400 761 M + H = 418769 M + H = 420 772 M + H = 438 775 M + H = 438

5. Separation of Compound 703 Enantiomers: Enantiomers 703A and 703B

The racemic compound of1-(3-fluoro-5-methoxypyridin-2-yl)-3-(oxetan-3-yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(80 mg, 0.18 mmol, 1.0 equiv) was purified by Chiral-Prep-HPLC with thefollowing conditions (Agela High-pressure Flash): Column, CHIRALPAK IC,2*25 cm, 5 um; mobile phase, Hex:DCM=3:1 and EtOH (1/1 for 19 min);Detector, UV254 nm) to afford 28 mg of (first eluted peak) Enantiomer703A and 28 mg of (second eluted peak) Enantiomer 703B as white solids.

Characterization of Enantiomer 703A. LCMS (ES) m/z 454 (M+H). ¹H NMR(300 MHz, Methanol-d₄) δ 8.08 (d, J=2.5 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H),7.52 (d, J=8.0 Hz, 2H), 7.42 (dd, J=11.0, 2.6 Hz, 1H), 5.00 (d, J=15.9Hz, 1H), 4.82 (t, J=7.0 Hz, 1H), 4.75 (d, J=17.3 Hz, 1H), 4.68-4.55 (m,3H), 4.49 (dd, J=12.6, 8.6 Hz, 2H), 4.47-4.36 (m, 1H), 3.93 (s, 3H),3.79 (dq, J=16.2, 7.8 Hz, 1H). Analytical chiral HPLC RT: 1.99 min(CHIRALPAK IC-3; 0.46 cm×5 cm; 3 micro; (Hex:DCM=3:1)(0.1%DEA):EtOH=50:50 at 1 ml/min).

Characterization of Enantiomer 703B. LCMS (ES) m/z 454 (M+H). ¹H NMR(300 MHz, Methanol-d₄) δ 8.08 (d, J=2.5 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H),7.52 (d, J=8.0 Hz, 2H), 7.42 (dd, J=11.0, 2.6 Hz, 1H), 5.00 (d, J=15.9Hz, 1H), 4.85-4.68 (m, 2H), 4.68-4.55 (m, 3H), 4.54-4.32 (m, 3H), 3.93(s, 3H), 3.79 (dq, J=16.2, 7.8 Hz, 1H). Analytical chiral HPLC RT: 2.63min (CHIRALPAK IC-3; 0.46 cm×5 cm; 3 micro; (Hex:DCM=3:1)(0.1%DEA):EtOH=50:50 at 1 ml/min).

The following compounds were prepared by methods analogous to the methoddescribed for Enantiomers 703A and 703B:

HPLC Separation Conditions Letter HPLC Conditions Q CHIRALPAK IE-3; 0.46cm × 5 cm; 3 micro; MtBE(0.1% DEA):EtOH = 50:50 at 1 ml/min U CHIRALPAKIE-3; 0.46 cm × 5 cm; 3 micro; MtBE(0.1% DEA):EtOH = 65:35 at 1 ml/minRetention Enantiomer LRMS (ES) Time No. m/z (min) HPLC 691A M + H = 4381.16 Q 691B M + H = 438 2.76 Q 711A M + H = 490 2.30 S 711B M + H = 4902.92 S 281A M + H = 457 1.20 T 281B M + H = 457 1.63 T 747A M + H = 4570.79 U 747B M + H = 457 1.66 U 758A M + H = 400 2.43 T 758B M + H = 4004.44 T 761A M + H = 418 1.41 U 761B M + H = 418 3.37 U 769A M + H = 4201.56 Q 769B M + H = 420 4.19 Q 772A M + H = 438 1.23 L 772B M + H = 4383.21 L 775A M + H = 438 1.32 Q 775B M + H = 438 3.32 Q

Example 68: Synthesis of Compound 739 1. Synthesis of Intermediate 68-1

The mixture of(1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutane-1-(680 mg, 3.17mmol, 1.0 equiv) and (4-(trifluoromethyl)phenyl)methanamine (556 mg,3.17 mmol, 1.0 equiv) in 2,2,2-trifluoroethanol (8.0 mL) was stirred atr.t. for 10 min. To this mixture were added5-chloro-3-fluoro-2-isocyanopyridine (500 mg, 3.17 mmol, 1.0 equiv) and2-chloroacetic acid (300 mg, 3.17 mmol, 1.0 equiv). The mixture wasstirred at r.t. for 3 h, evaporated, purified with 20% EA/Hex to afford933 mg (47%) of2-((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-N-(5-chloro-3-fluoropyridin-2-yl)-2-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)acetamide(Intermediate 68-1). LRMS (APCI) m/z 623.1 (M+H).

2. Synthesis of Intermediate 68-2

To a solution of2-((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-N-(5-chloro-3-fluoropyridin-2-yl)-2-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)acetamide(933 mg, 1.5 mmol, 1.0 equiv) in DMF (10 mL) was added K₂CO₃ (626 mg,4.5 mmol, 3.0 equiv). The resulting mixture was stirred at 80° C. for 15min, cooled to r.t., diluted with EA (100 mL), washed with water (50 mL)three times and brine (50 mL) once, dried over sodium sulfate, andconcentrated under reduced pressure to afford 760 mg (87%) of3-((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1-(5-chloro-3-fluoropyridin-2-O-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Intermediate 68-2) as a white foam. LRMS (APCI) m/z 586.1 (M+H).

3. Synthesis of Compound 739

To a solution of3-((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1-(5-chloro-3-fluoropyridin-2-yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(760 mg, 1.30 mmol, 1.0 equiv) in THF (10 mL) was added TBAF (2.59 mL of1.0 M in THF, 2.59 mmol, 2.0 equiv). The resulting mixture was stirredat r.t. for 30 min, quenched with saturated aqueous sodium bicarbonate(30 mL), and diluted with DCM (125 mL). The organic phase was washedwith brine (75 mL), dried over sodium sulfate, concentrated in vacuo,and purified with silica gel using a gradient from 0-100% EA/Hex toafford 420 mg (69%) of 1-(5-chloro-3-fluoropyridin-2-yl)-3-((1s,3s)-3-hydroxycyclobutyl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Compound 739) as a white foam. (LRMS (APCI) m/z 472.0 (M+H). ¹H NMR(400 MHz, DMSO-d₆) δ 8.49 (d, J=2.1 Hz, 1H), 8.26 (dd, J=9.4, 2.1 Hz,1H), 7.75 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H), 5.10-5.01 (m, 2H),4.75 (d, J=17.0 Hz, 1H), 4.37 (dd, J=17.0, 13.5 Hz, 2H), 4.05 (d, J=8.0Hz, 1H), 3.92-3.81 (m, 1H), 2.35-2.14 (m, 3H), 1.76 (m, 2H).

Example 69: Synthesis of Compound 740 1. Synthesis of Intermediate 69-1

The mixture of(1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutane-1-carbaldehyde (680mg, 3.17 mmol, 1.0 equiv) and (4-(trifluoromethyl)phenyl)methanamine(556 mg, 3.17 mmol, 1.0 equiv) in 2,2,2-trifluoroethanol (8.0 mL) wasstirred at r.t. for 10 min. To this mixture were added5-chloro-3-fluoro-2-isocyanopyridine (500 mg, 3.17 mmol, 1.0 equiv) and2-chloroacetic acid (300 mg, 3.17 mmol, 1.0 equiv). The mixture wasstirred at r.t. for 3 h, evaporated, purified with 20% EA/Hex to afford1.2 g (59%) of2-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-N-(5-chloro-3-fluoropyridin-2-yl)-2-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)acetamide(Intermediate 69-1; racemic mixture of cis and trans isomer) as a whitefoam. LRMS (APCI) m/z 623.1 (M+H).

2. Synthesis of Intermediate 69-2

To a solution of2-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-N-(5-chloro-3-fluoropyridin-2-yl)-2-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)acetamide(1.2 g, 2.0 mmol, 1.0 equiv) in DMF (10 mL) was added K₂CO₃ (781 mg, 5.6mmol, 3.0 equiv). The resulting mixture was stirred at 80° C. for 15min, cooled to r.t., diluted with EA (100 mL), washed with water (50 mL)three times and brine (50 mL) once, dried over sodium sulfate, andconcentrated under reduced pressure to afford 988 mg (90%) of3-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1-(5-chloro-3-fluoropyridin-2-yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Intermediate 69-2; racemic mixture of cis and trans-isomers) as a whitefoam. LRMS (APCI) m/z 586.1 (M+H).

3. Synthesis of Compound 740

To a solution of3-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1-(5-chloro-3-fluoropyridin-2-yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(988 mg, 1.69 mmol, 1.0 equiv) in THF (10 mL) was added TBAF (3.37 mL of1.0 M in THF, 3.37 mmol, 2.0 equiv). The resulting mixture was stirredat r.t. for 30 min, quenched with saturated aqueous sodium bicarbonate(30 mL), and diluted with DCM (125 mL). The organic phase was washedwith brine (75 mL), dried over sodium sulfate, concentrated in vacuo,and purified with silica gel using a gradient from 0% EA/Hex to 100%EA/Hex to afford 530 mg (66%) of1-(5-chloro-3-fluoropyridin-2-yl)-3-(3-hydroxycyclobutyl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Compound 740; 1:1 mixture of cis and trans-isomers) as a white foam.LRMS (APCI) m/z 472.0 (M+H).

4. Separation of Compound 740 Stereoisomers: Stereoisomers 740A, 740B,740C, and 740D

The stereoisomers of1-(4-chloro-2-fluorophenyl)-3-(3-hydroxycyclobutyl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(796 mg) was purified by Chiral-Prep-HPLC with the following conditions:Column, CHIRALPAK IG, 2*25 cm, 5 um; mobile phase, hexane (8 mMNH₃/MeOH) and EtOH (hold 35% EtOH for 18 min); Detector, UV 254 nm/220nm) to afford 150 mg of Stereoisomer 740C, 96 mg of Stereoisomer 740D,and 250 mg mixture of Stereoisomer 740A and Stereoisomer 740B, which wasfurther purified by Chiral HPLC with the following condition; ColumnCHIRALPAK IG 20*25 cm, 5 um; mobile phase, hexane (8 mM NH₃/MeOH) andEtOH (hold 35% EtOH for 18 min); Detector, UV 254 nm/220 nm)) to afford63 mg of Stereoisomer 740B and 118 mg of Stereoisomer 740A as whitesolids.

Characterization of Stereoisomer 740A. LCMS (ES) m/z 472 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 8.47 (d, J=2.1 Hz, 1H), 8.24 (dd, J=9.4, 2.2 Hz,1H), 7.73 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 5.12-5.00 (m, 2H),4.74 (d, J=17.0 Hz, 1H), 4.36 (dd, J=16.3, 9.8 Hz, 2H), 4.04 (d, J=7.7Hz, 1H), 3.86 (q, J=6.6 Hz, 1H), 2.22 (dp, J=17.1, 6.6 Hz, 3H), 1.73 (q,J=9.4 Hz, 2H). Analytical chiral HPLC RT: 0.85 min (CHIRALPAK IG-3; 0.46cm×5 cm; 3 micro; MtBE (0.1% DEA):EtOH=60:40 at 1 ml/min).

Characterization of Stereoisomer 740B. LCMS (ES) m/z 472 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 8.47 (d, J=2.1 Hz, 1H), 8.25 (dd, J=9.4, 2.2 Hz,1H), 7.72 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 5.09-4.97 (m, 2H),4.78 (d, J=17.1 Hz, 1H), 4.49 (d, J=15.7 Hz, 1H), 4.35 (d, J=17.1 Hz,1H), 4.18 (t, J=8.7 Hz, 2H), 2.95 (s, 1H), 2.23 (s, 2H), 1.87 (td,J=8.8, 4.4 Hz, 2). Analytical chiral HPLC RT: 0.82 min (CHIRALPAK IG-3;0.46 cm×5 cm; 3 micro; MtBE (0.1% DEA):EtOH=60:40 at 1 ml/min).

Characterization of Stereoisomer 740C. LCMS (ES) m/z 472 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 8.47 (d, J=2.1 Hz, 1H), 8.24 (dd, J=9.4, 2.1 Hz,1H), 7.73 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 5.11-5.00 (m, 2H),4.74 (d, J=16.9 Hz, 1H), 4.36 (dd, J=16.3, 10.0 Hz, 2H), 4.04 (d, J=7.7Hz, 1H), 3.87 (p, J=7.1 Hz, 1H), 2.35-2.12 (m, 2H), 2.20 (s, 1H), 1.73(q, J=9.4 Hz, 2H). Analytical chiral HPLC RT: 1.56 min (CHIRALPAK IG-3;0.46 cm×5 cm; 3 micro; MtBE (0.1% DEA):EtOH=60:40 at 1 ml/min).

Characterization of Stereoisomer 740D. LCMS (ES) m/z 472 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 8.47 (t, J=1.9 Hz, 1H), 8.25 (dt, J=9.4, 1.8 Hz,1H), 7.72 (d, J=7.9 Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 5.09-4.97 (m, 2H),4.78 (d, J=17.1 Hz, 1H), 4.49 (d, J=15.7 Hz, 1H), 4.35 (d, J=17.1 Hz,1H), 4.24-4.12 (m, 2H), 2.95 (d, J=9.3 Hz, 1H), 2.28-2.17 (m, 2H),1.94-1.80 (m, 2H). Analytical chiral HPLC RT: 2.98 min (CHIRALPAK IG-3;0.46 cm×5 cm; 3 micro; MtBE (0.1% DEA):EtOH=60:40 at 1 ml/min).

Example 70: Synthesis of Compound 750 1. Synthesis of Intermediate 70-1

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylaceticacid (1.0 g, 4.6 mmol, 1.0 equiv) in DCM (50.0 mL) were added EDCI (1.8g, 9.3 mmol, 2.0 equiv.), HOBt (0.63 g, 4.6 mmol, 1.0 equiv.), and TEA(1.3 mL, 9.3 mmol, 2.0 equiv.). After stirring at r.t. for 5 min, tothis mixture was added 5-chloro-3-fluoropyridin-2-amine (0.8 g, 5.6mmol, 1.2 equiv.). The mixture continued to stir for overnight,concentrated to dryness, diluted with EA, washed with water and brine,dried over Na₂SO₄, concentrated under reduced pressure, and purified bysilica gel using EA/HE as eluent to afford 730 mg (46%) of tert-butyl(S)-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-cyclopropyl-2-oxoethyl)carbamate(Intermediate 70-1) as a white solid. LRMS (ES) m/z 344.1 (M+H).

2. Synthesis of Intermediate 70-2

To a solution of tert-butyl(S)-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-cyclopropyl-2-oxoethyl)carbamate(560 mg, 1.6 mmol, 1.0 equiv) in DCM (10.0 mL) at r.t was added TFA (2.0mL). The mixture was stirred at rt for 1 h and concentrated to drynessto afford 550 mg (98%) of(S)-2-amino-N-(5-chloro-3-fluoropyridin-2-yl)-2-cyclopropylacetamide2,2,2-trifluoroacetate (Intermediate 70-2). LRMS (ES) m/z 244.0 (M+H).

3. Synthesis of Intermediate 70-3

To a solution of(S)-2-amino-N-(5-chloro-3-fluoropyridin-2-yl)-2-cyclopropylacetamide2,2,2-trifluoroacetate (280 mg, 0.8 mmol, 1.0 equiv) in DCM (5.0 mL) atr.t was added 4-(trifluoromethyl)benzaldehyde (177 mg, 1.0 mmol, 1.3equiv). After stirring at rt for 5 min, to this mixture was added STAB(497 mg, 2.3 mmol, 3.0 equiv.). The mixture was for 4 h at rt, quenchedwith addition of HCl (1N) until Ph reached to 1-2, stirred for 10 min,basified to pH 9-10 with sat. sodium bicarbonate solution, and extractedwith DCM five times. The combined organic extracts were dried overMgSO₄, concentrated, and purified by silica gel using a gradient of20-100% EA/HE as eluent to afford 300 mg (95%) of(S)—N-(5-chloro-3-fluoropyridin-2-yl)-2-cyclopropyl-2-((4-(trifluoromethyl)benzyl)amino)acetamide(Intermediate 70-3). LRMS (ES) m/z 402 (M+H).

4. Synthesis of Intermediate 70-4

To a solution of(S)—N-(5-chloro-3-fluoropyridin-2-yl)-2-cyclopropyl-2-((4-(trifluoromethyl)benzyl)amino)acetamide(300 mg, 0.7 mmol, 1.0 equiv) in DCM (10.0 mL) cooled to 0° C. wereadded 2-chloroacetyl chloride (110 mg, 1.0 mmol, 1.3 equiv) and TEA (0.2mL, 1.5 mmol, 2.0 equiv.). The mixture was stirred at 0° C. for 30 min,quenched with sat. NH₄Cl solution, and extracted with DCM twice. Thecombined organic extracts were dried over MgSO₄ and concentrated toafford 350 mg of(S)-2-chloro-N-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-cyclopropyl-2-oxoethyl)-N-(4-(trifluoromethyl)benzyl)acetamide(Intermediate 70-4). LRMS (ES) m/z 478 (M+H).

5. Synthesis of Compound 750

To a solution of(S)-2-chloro-N-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-cyclopropyl-2-oxoethyl)-N-(4-(trifluoromethyl)benzyl)acetamide(350 mg, 0.7 mmol, 1.0 equiv) in DMF (5.0 mL) at r.t was added K₂CO₃(204 mg, 1.5 mmol, 2.0 equiv). The mixture was stirred at 80° C. for 1h, cooled, diluted with EA, filtered through celite, concentrated, andpurified by reverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm,gradient over 10-100% acetonitrile in water both with 0.1% formic acidgradient in 30 min) to afford 34 mg (10% over two steps) of(S)-1-(5-chloro-3-fluoropyridin-2-yl)-3-cyclopropyl-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Compound 750). LRMS (ES) m/z 442 (M+H). ¹H NMR (400 MHz, MethyleneChloride-d₂) δ 8.22 (d, J=2.1 Hz, 1H), 7.58-7.47 (m, 3H), 7.34 (d, J=8.0Hz, 2H), 5.18 (d, J=15.6 Hz, 1H), 4.59 (d, J=17.0 Hz, 1H), 4.45-4.29 (m,2H), 3.25 (d, J=8.7 Hz, 1H), 1.15-1.02 (m, 1H), 0.67-0.45 (m, 3H),0.38-0.27 (m, 1H).

The following compound was prepared by methods analogous to the methoddescribed for Compound 750:

Compound No. LRMS (ES) m/z 751 M + H = 392.0

Example 71: Synthesis of Diastereomer 875A 1. Synthesis of IntermediateDiastereomer 71-2A

To a solution of Intermediate Diastereomer 71-1A (800 mg, 1.4 mmol, 1.0equiv) in DMF (3.0 mL) at r.t was added K₂CO₃ (397 mg, 2.9 mmol, 2.0equiv). The mixture was stirred at 80° C. for 30 min, cooled to rt,filtered, and purified by reverse phase HPLC (Phenomenex, gemini 5u C18150×21.2 mm, 40-100% acetonitrile in water both with 0.1% formic acidgradient over 25 min) to afford 510 mg, 68% of a diastereomer oftert-butyl8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)-6,9-dioxo-5,8-diazaspiro[3.5]nonane-2-carboxylate(Intermediate Diastereomer 71-2A). LRMS (ES) m/z 468 (M+H-^(t)Bu). Asused in this example, the dashed bond --- indicates that thestereochemical configuration of the starting material is retained in theproduct compound.

2. Synthesis Intermediate Diastereomer 71-3A

To a solution of Intermediate Diastereomer 71-2A (510 mg, 1.0 mmol, 1.0equiv) in DCM (5.0 mL) at r.t was added TFA (1.0 mL). The mixture wasstirred at rt for 30 min and concentrated to obtain the correspondingacid as a diastereomer of8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)-6,9-dioxo-5,8-diazaspiro[3.5]nonane-2-carboxylicacid (Intermediate Diastereomer 71-3A), which was used for next stepwithout further purification.

3. Synthesis of Intermediate Diastereomer 71-4A

To a solution of Intermediate Diastereomer 71-3A (455 mg, 1.0 mmol, 1.0equiv) in DCM (5.0 mL) at r.t were added oxalyl chloride (1.0 mL) andone drop of DMF. The mixture was stirred at rt for 30 min andconcentrated to obtain a diastereomer of8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)-6,9-dioxo-5,8-diazaspiro[3.5]nonane-2-carbonylchloride (Intermediate Diastereomer 71-4A), which was used for next stepwithout further purification.

4. Synthesis of Diastereomer 875A

To a solution of Intermediate Diastereomer 71-4A (472 mg, 1.0 mmol, 1.0equiv) in DCM (10.0 mL) at r.t was added ammonium hydroxide (1.0 mL, 30%wt). The mixture was stirred at rt for 30 min, concentrated, andpurified by reverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm,10-100% acetonitrile in water both with 0.1% formic acid gradient over25 min) to afford 121 mg (27% over three steps) of a diastereomer of8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)-6,9-dioxo-5,8-diazaspiro[3.5]nonane-2-carboxamide(Diastereomer 875A). LRMS (ES) m/z 467 (M+H). ¹H NMR (400 MHz, MethyleneChloride-d₂) δ 8.36 (s, 1H), 7.71-7.63 (d, J=8.0 Hz, 1H), 7.53 (d, J=7.9Hz, 2H), 7.39 (d, J=7.9 Hz, 2H), 6.70 (t, J=56.4 Hz, 1H), 5.58 (s, 1H),5.51 (s, 1H), 5.13 (s, 2H), 4.55 (s, 2H), 3.04 (p, J=8.5 Hz, 1H),2.90-2.76 (m, 4H), 2.01 (s, 3H).

The following compounds were prepared by methods analogous to the methoddescribed for Diastereomer 875A:

Diastereomer LRMS (ES) No. m/z ¹H NMR 870A M + H = 499 (400 MHz,Methylene Chloride-d2) δ 8.36 (d, J = 2.0 Hz, 1H), 7.71-7.59 (m, 3H),7.45 (d, J = 8.0 Hz, 2H), 5.47 (br, 1H), 5.20 (s, 2H), 4.55 (s, 2H),3.05-2.69 (m, 8H). 871A M + H = 513 (400 MHz, Methylene Chloride-d2) δ8.37 (d, J = 2.0 Hz, 1H), 7.71-7.61 (m, 3H), 7.43 (d, J = 8.0 Hz, 2H),5.10 (s, 2H), 4.56 (s, 2H), 3.41-3.27 (m, 1H), 2.92 (d, J = 5.6 Hz, 6H),2.84 (d, J = 8.9 Hz, 4H). 872A M + H = 451 (400 MHz, MethyleneChloride-d2) δ 8.36 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 9.0, 2.0 Hz, 1H),7.36 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 5.43 (s, 1H), 5.32(s, 1H), 5.05 (s, 2H), 4.54 (s, 2H), 3.03 (p, J = 8.5 Hz, 1H), 2.83 (t,J = 7.3 Hz, 4H). 873A M + H = 465 (400 MHz, Methylene Chloride-d₂) δ8.23 (s, 1H), 7.57-7.50 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H),7.14 (d, J = 8.2 Hz, 2H), 5.43 (s, 1H), 4.96 (s, 2H), 4.40 (s, 2H),2.84-2.68 (m, 3H), 2.71-2.59 (m, 5H). 874A M + H = 479 (400 MHz,Methylene Chloride-d₂) δ 8.23 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.9,2.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 4.86(s, 2H), 4.40 (s, 2H), 3.19 (p, J = 8.7 Hz, 1H), 2.81 (s, 3H), 2.78 (d,J = 0.9 Hz, 3H), 2.70 (d, J = 8.8 Hz, 4H). 876A M + H = 435.0 (400 MHz,Methylene Chloride-d₂) δ 8.23 (s, 1H), 7.53 (d, J = 8.9 Hz, 1H),7.21-7.13 (m, 2H), 6.94 (t, J = 8.5 Hz, 2H), 5.30 (s, 1H), 5.19 (s, 1H),4.91 (s, 2H), 4.40 (s, 2H), 2.97-2.84 (m, 1H), 2.79-2.63 (m, 4H).

Example 72: Synthesis of Diastereomer 875B 1. Synthesis of IntermediateDiastereomer 71-2B

To a solution of Intermediate Diastereomer 71-2B (1000 mg, 1.8 mmol, 1.0equiv) in DMF (3.0 mL) at r.t was added K₂CO₃ (497 mg, 3.6 mmol, 2.0equiv). The mixture was stirred at 80° C. for 30 min, cooled to rt,filtered, and purified by reverse phase HPLC (Phenomenex, gemini 5u C18150×21.2 mm, 40-100% acetonitrile in water both with 0.1% formic acidgradient over 25 min) to afford 680 mg, 72% of a diastereomer oftert-butyl8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)-6,9-dioxo-5,8-diazaspiro[3.5]nonane-2-carboxylate(Intermediate Diastereomer 71-2B). LRMS (ES) m/z 524 (M+H). As used inthis example, the dashed bond --- indicates that the stereochemicalconfiguration of the starting material is retained in the productcompound.

2. Synthesis of Intermediate Diastereomer 71-3B

To a solution of Intermediate Diastereomer 71-2B (680 mg, 1.3 mmol, 1.0equiv) in DCM (5.0 mL) at r.t was added TFA (1.0 mL). The mixture wasstirred at rt for 30 min and concentrated to obtain the correspondingacid as a diastereomer of8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)-6,9-dioxo-5,8-diazaspiro[3.5]nonane-2-carboxylicacid (Intermediate Diastereomer 71-3B), which was used for next stepwithout further purification.

3. Synthesis of Intermediate Diastereomer 71-4B

To a solution of Intermediate Diastereomer 71-3B (606 mg, 1.0 mmol, 1.0equiv) in DCM (5.0 mL) at r.t were added oxalyl chloride (1.0 mL) andone drop of DMF. The mixture was stirred at rt for 30 min andconcentrated to obtain the corresponding acid chloride as a diastereomerof8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)-6,9-dioxo-5,8-diazaspiro[3.5]nonane-2-carbonylchloride (Intermediate Diastereomer 71-4B), which was used for next stepwithout further purification.

4. Synthesis of Diastereomer 875B

To a solution of Intermediate Diastereomer 71-4B (626 mg, 1.0 mmol, 1.0equiv) in DCM (10.0 mL) at r.t was added ammonium hydroxide (1.5 mL, 30%wt). The mixture was stirred at rt for 30 min, concentrated, andpurified by reverse phase HPLC (Phenomenex, gemini 5u C18 150×21.2 mm,10-100% acetonitrile in water both with 0.1% formic acid gradient over25 min) to afford 340 mg (57% over three steps) of a diastereomer of8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)-6,9-dioxo-5,8-diazaspiro[3.5]nonane-2-carboxamide(Diastereomer 875B). LRMS (ES) m/z 467 (M+H). ¹H NMR (400 MHz, MethyleneChloride-d₂) δ 8.36 (d, J=1.8 Hz, 1H), 7.67 (dd, J=9.0, 2.1 Hz, 1H),7.56 (d, J=7.9 Hz, 2H), 7.41 (d, J=7.9 Hz, 2H), 6.71 (t, J=56.4 Hz, 1H),6.32 (s, 1H), 5.52 (s, 1H), 5.03 (s, 2H), 4.56 (s, 2H), 3.22-3.11 (m,2H), 3.10-2.96 (m, 1H), 2.82-2.71 (m, 2H).

The following compounds were prepared by methods analogous to the methoddescribed for Diastereomer 875B:

Diastereomer LRMS (ES) No. m/z ¹H NMR 870B M + H = 499 (400 MHz,Methylene Chloride-d₂) δ 8.36 (d, J = 2.0 Hz, 1H), 7.71-7.63 (m, 3H),7.43 (d, J = 8.0 Hz, 2H), 6.25 (s, 1H), 5.04 (s, 2H), 4.55 (s, 2H),3.21-3.11 (m, 2H), 3.09-2.96 (m, 1H), 2.79-2.65 (m, 5H). 871B M + H =513 (400 MHz, Methylene Chloride-d₂) δ 8.34 (d, J = 2.0 Hz, 1H),7.72-7.61 (m, 3H), 7.46 (d, J = 8.0 Hz, 2H), 5.08 (s, 2H), 4.55 (s, 2H),3.28 (dd, J = 13.8, 8.0 Hz, 2H), 3.00 (p, J = 8.9 Hz, 1H), 2.83 (br,6H), 2.65-2.54 (m, 2H). 872B M + H = 451 (400 MHz, MethyleneChloride-d₂) δ 8.23 (d, J = 2.0 Hz, 1H), 7.54 (dt, J = 9.0, 1.6 Hz, 1H),7.26 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 6.17 (s, 1H), 5.23(s, 1H), 4.82 (s, 2H), 4.41 (d, J = 1.1 Hz, 2H), 3.08-2.98 (m, 2H),2.95-2.82 (m, 1H), 2.70-2.59 (m, 2H). 873B M + H = 465 (400 MHz,Methylene Chloride-d₂) δ 8.35 (d, J = 1.9 Hz, 1H), 7.67 (dd, J = 9.0,2.0 Hz, 1H), 7.38 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 6.20(s, 1H), 4.95 (s, 2H), 4.53 (s, 2H), 3.18-3.08 (m, 2H), 3.04-2.90 (m,1H), 2.79-2.66 (m, 5H). 874B M + H = 479 (400 MHz, MethyleneChloride-d₂) δ 8.20 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 8.9, 2.1 Hz, 1H),7.26 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 4.85 (s, 2H), 4.40(s, 2H), 3.18-3.07 (m, 2H), 2.90-2.76 (m, 1H), 2.76 (s, 3H), 2.64 (s,3H), 2.53-2.42 (m, 2H). 876B M + H = 435.0 (400 MHz, MethyleneChloride-d₂) δ 8.35 (d, J = 1.8 Hz, 1H), 7.66 (dd, J = 8.8, 2.2 Hz, 1H),7.31 (dd, J = 8.2, 5.3 Hz, 2H), 7.10 (t, J = 8.5 Hz, 2H), 6.33 (s, 1H),5.56 (s, 1H), 5.36 (s, 0H), 4.95 (s, 2H), 4.54 (s, 2H), 3.20-3.10 (m,2H), 3.07-2.93 (m, 1H), 2.83-2.72 (m, 2H). 877B M + H = 485 (400 MHz,Methylene Chloride-d2) δ 8.36 (d, J = 2.0 Hz, 1H), 7.71-7.63 (m, 3H),7.44 (d, J = 8.0 Hz, 2H), 6.30 (s, 1H), 5.44 (s, 1H), 5.04 (s, 2H), 4.56(s, 2H), 3.23-3.13 (m, 2H), 3.05 (qd, J = 10.3, 6.8 Hz, 1H), 2.81-2.70(m, 2H).

Example 73: Synthesis of Compound 784 1. Synthesis of Intermediate 73-1

To a solution of (4-(trifluoromethyl)phenyl)methanamine (568 mg, 3.2mmol, 1.0 equiv) in 2,2,2-trifluoroethanol (5.0 mL) was added methyl3-formylbicyclo[1.1.1]pentane-1-carboxylate (500 mg, 3.2 mmol, 1.0equiv). After stirring at r.t. for 10 min, to this resulting mixturewere added 5-chloro-3-fluoro-2-isocyanopyridine (511 mg, 3.2 mmol, 1.0equiv) and chloroacetic acid (337 mg, 3.6 mmol, 1.1 equiv). Theresulting mixture was stirred at r.t. overnight, concentrated underreduced pressure, and purified silica gel chromatography, eluted withEA/HE to afford 1.8 g (99%) of methyl3-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-2-oxoethyl)bicyclo[1.1.1]pentane-1-carboxylate(Intermediate 73-1) as a foam. LRMS (ES) m/z 562 (M+H).

2. Synthesis of Intermediate 73-2

To a solution of methyl3-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-2-oxoethyl)bicyclo[1.1.1]pentane-1-carboxylate(1.8 g, 3.2 mmol, 1.0 equiv) in DMF (5.0 mL) at r.t was added K₂CO₃ (0.9g, 6.4 mmol, 2.0 equiv). The mixture was stirred at 80° C. for 30 min,diluted with EA (20 mL), filtered, and concentrated. The residue wastriturated with ACN to afford 1.2 g (71%) of methyl3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)bicyclo[1.1.1]pentane-1-carboxylate(Intermediate 73-2). LRMS (ES) m/z 526.1 (M+H). ¹H NMR (400 MHz,Methylene Chloride-d₂) δ 8.31 (d, J=2.0 Hz, 1H), 7.68-7.57 (m, 3H), 7.43(d, J=8.0 Hz, 2H), 5.45 (d, J=15.3 Hz, 1H), 4.50 (s, 2H), 4.04 (s, 1H),4.01 (d, J=15.3 Hz, 1H), 3.66 (s, 3H), 2.16 (s, 6H).

3. Synthesis of Intermediate 73-3

To a solution of methyl3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)bicyclo[1.1.1]pentane-1-carboxylate(1.2 g, 2.3 mmol, 1.0 equiv) in dioxane (2.0 mL) at r.t was added LiOH(2.3 mL, 2 N, 4.6 mmol, 2.0 equiv.). The mixture was stirred at rt for30 min, acidified to pH 1-3, and extracted with EA three times. Thecombined extracts were washed with brine, dried over MgSO₄, andconcentrated to afford 1.16 g (99%) of3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)bicyclo[1.1.1]pentane-1-carboxylicacid (Intermediate 73-3). LRMS (ES) m/z 512 (M+H). ¹H NMR (400 MHz,Chloroform-d) δ 8.23 (d, J=2.1 Hz, 1H), 7.59-7.48 (m, 3H), 7.31 (d,J=8.0 Hz, 2H), 5.43 (d, J=15.2 Hz, 1H), 4.44 (s, 2H), 3.97 (s, 1H), 3.89(d, J=15.2 Hz, 1H), 2.14 (s, 6H).

4. Synthesis of Intermediate 73-4

To a solution of3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)bicyclo[1.1.1]pentane-1-carboxylicacid (80 mg, 0.16 mmol, 1.0 equiv) in DCM (6.0 mL) at r.t were addedoxalyl chloride (0.5 mL) and one drop of DMF. The mixture was stirred atrt for 30 min and concentrated to obtain3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)bicyclo[1.1.1]pentane-1-carbonylchloride (Intermediate 73-4), which was used for next step withoutfurther purification.

5. Synthesis of Compound 784

To a solution of3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)bicyclo[1.1.1]pentane-1-carbonylchloride (0.16 mmol, 1.0 equiv) in THF (6.0 mL) cooled to 0° C. wasadded sodium borohydride (12 mg, 0.31 mmol, 2.0 equiv.). The mixture wasstirred at 0° C. for 30 min, acidified to pH 1-3 with HCl (1 N), andextracted with EA three times. The combined extracts were washed withbrine, dried over MgSO₄, concentrated, and purified by reverse phaseHPLC (Phenomenex, gemini 5u C18 150×21.2 mm, gradient over 10-100%acetonitrile in water both with 0.1% formic acid in 25 min) to afford 14mg (18% over two steps) of1-(5-chloro-3-fluoropyridin-2-yl)-3-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Compound 784). LRMS (ES) m/z 498.1 (M+H). ¹H NMR (400 MHz,Chloroform-d) δ 8.22 (d, J=2.1 Hz, 1H), 7.58-7.46 (m, 3H), 7.31 (d,J=8.0 Hz, 2H), 5.45 (d, J=15.2 Hz, 1H), 4.42 (q, J=15.1 Hz, 2H), 3.95(s, 1H), 3.89 (d, J=15.1 Hz, 1H), 3.57 (d, J=4.1 Hz, 2H), 1.78 (s, 6H).

Example 74: Synthesis of Compound 866 1. Synthesis of Intermediate 74-1

A mixture of Ac₂O (14 g, 137 mmol, 4.0 equiv) and formic acid (154 g,154 mmol, 4.5 equiv.) was stirred at 55° C. for 2 h. To the mixturecooled to 0° C. was added 4-chloro-2-fluoroaniline (5 g, 34.4 mmol, 1.0equiv.) dropwise. The mixture was stirred at r.t. for 2 h, concentratedunder reduced pressure, and triturated with Et₂O to afford 5.3 g (84%)of N-(4-chloro-2-fluorophenyl)formamide (Intermediate 74-1) as a whitesolid. LRMS (ES) m/z 174 (M+H). ¹H NMR (NMR (300 MHz, DMSO-d₆) δ 10.23(s, 1H), 8.31 (s, 1H), 8.13 (t, J=8.7 Hz, 1H), 7.56-7.36 (m, 1H), 7.25(ddd, J=8.8, 2.4, 1.3 Hz, 1H).

2. Synthesis of Intermediate 74-2

To a stirred solution of N-(4-chloro-2-fluorophenyl)formamide (5.1 g,29.4 mmol, 1.0 equiv.) and TEA (9.0 g, 87.9 mmol, 6 equiv.) in DCM (100mL) cooled to 0° C. was added triphosgene (3.8 g, 12.6 mmol, 0.43equiv.) in DCM (20 mL) dropwise over a period of 10 min. The mixture wasstirred at r.t. overnight, cooled to 0° C., quenched with MeOH,concentrated under reduced pressure, and purified by silica gel usingPE/EA (10/1) as eluent to afford 13 g (27% pure) of4-chloro-2-fluoro-1-isocyanobenzene (Intermediate 74-2) as a yellowsolid. LRMS (ES) m/z 156 (M+H).

3. Synthesis of Intermediate 74-3

To a stirred solution of 3-(benzyloxy)cyclobutane-1-carboxylic acid (6.5g, 31.5 mmol, 1.0 equiv.) in THF (50 mL) cooled to 0° C. was addedBH₃-THF (1 M in THF, 157.6 mL, 157.6 mmol, 5.0 equiv.) dropwise over aperiod of 1 h. The mixture was stirred at rt overnight, cooled to 0° C.,quenched with MeOH, and concentrated under reduced pressure to afford6.9 g of (3-(benzyloxy)cyclobutyl)methanol (Intermediate 74-3) as ayellow solid. LRMS (ES) m/z 193 (M+H).

4. Synthesis of Intermediate 74-4

To a solution of PCC (11.4 g, 53.1 mmol, 1.5 equiv.) in DCM (70 mL) wasadded celite (13 g, 216.3 mmol, 6.1 equiv.). After stirring at rt for 30min, to this mixture was added (3-(benzyloxy)cyclobutyl)methanol (6.8 g,35.3 mmol, 1.0 equiv.). The mixture was stirred at rt for 2 h, dilutedwith Et₂O (140 mL), filtered off solid, and concentrated under reducedpressure to afford 6 g of 3-(benzyloxy)cyclobutane-1-carbaldehyde(Intermediate 74-4) as a yellow solid. LRMS (ES) m/z 191 (M+H).

5. Synthesis of Intermediate 74-5

To a solution of 4-fluorophenylmethanamine (441 mg, 3.5 mmol, 1.0 equiv)in 2,2,2-trifluoroethanol (10.0 mL) was added3-(benzyloxy)cyclobutane-1-carbaldehyde (673 mg, 3.5 mmol, 1.0 equiv).After stirring at r.t. for 10 min, to this resulting mixture were added4-chloro-2-fluoro-1-isocyanobenzene (1.85 g, 27% pure, 3.2 mmol, 1.0equiv) and chloroacetic acid (331 mg, 3.5 mmol, 1.0 equiv). Theresulting mixture was stirred at r.t. overnight, concentrated underreduced pressure, and purified silica gel chromatography, eluted withEA/PE (1/6) to afford 1.1 g of2-(3-(benzyloxy)cyclobutyl)-N-(4-chloro-2-fluorophenyl)-2-(2-chloro-N-(4-fluorobenzyl)acetamido)acetamide(Intermediate 74-5) as a yellow oil. LRMS (ES) m/z 562 (M+H).

6. Synthesis of Intermediate 74-6

To a solution of2-(3-(benzyloxy)cyclobutyl)-N-(4-chloro-2-fluorophenyl)-2-(2-chloro-N-(4-fluorobenzyl)acetamido)acetamide(1.1 g, 2.0 mmol, 1.0 equiv) in DMF (15.0 mL) at r.t was added K₂CO₃(555 mg, 4.0 mmol, 2.0 equiv). The mixture was stirred at rt for 30 min,diluted water (30 mL), and extracted with EA (30 mL) twice. The combinedorganic layers were washed with brine (30 mL) twice, dried over Na₂SO₄,and concentrated under reduced pressure to afford 1 g of3-(3-(benzyloxy)cyclobutyl)-1-(4-chloro-2-fluorophenyl)-4-(4-fluorobenzyl)piperazine-2,5-dione(Intermediate 74-6). LRMS (ES) m/z 511 (M+H).

7. Synthesis of Compound 866

A solution of3-(3-(benzyloxy)cyclobutyl)-1-(4-chloro-2-fluorophenyl)-4-(4-fluorobenzyl)piperazine-2,5-dione(700 mg, 1.4 mmol, 1.0 equiv) in HCl (6 N, 15 mL) was stirred at 100° C.overnight, cooled to r.t., concentrated under reduced pressure, dilutedwith water, adjusted the pH to 9 with sodium bicarbonate, and extractedwith EA (20 mL) twice. The combined organic layer was washed with brine(20 mL), dried over Na₂SO₄, concentrated under reduced pressure, andpurified by Prep-HPLC with the following conditions: (SHIMADZU(HPLC-01)): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobilephase, Water (10 mM NH₄HCO₃) and ACN (25% gradient to 50% in 8 min);Detector UV 254 nm) to afford 230 mg of1-(4-chloro-2-fluorophenyl)-4-(4-fluorobenzyl)-3-(3-hydroxycyclobutyl)piperazine-2,5-dione(Compound 866). LRMS (ES) m/z 421 (M+H).

8. Separation of Compound 866 Stereoisomers: Stereoisomers 866A, 866B,866C, and 866D

The stereoisomers of1-(4-chloro-2-fluorophenyl)-4-(4-fluorobenzyl)-3-(3-hydroxycyclobutyl)piperazine-2,5-dione(230 mg, 0.55 mmol, 1.0 equiv) was purified by Chiral-Prep-HPLC with thefollowing conditions: Column, CHIRALPAK IF, 2*25 cm, 5 um; mobile phase,MTBE (10 mM NH₃/MeOH) and EtOH (hold 5% EtOH for 13 min); Detector, UV254 nm/220 nm) to afford 86 mg of Stereoisomer 866A, 23 mg ofStereoisomer 866D, and 100 mg mixture of Stereoisomer 866B andStereoisomer 866C, which was further purified by Chiral HPLC with thefollowing condition; Column CHIRALPAK IG 20*25 cm, 5 um; mobile phase,MTBE (10 mM NH₃/MeOH) and EtOH (hold 30% EtOH for 10 min); Detector, UV254 nm/220 nm) to afford 68 mg of Stereoisomer 866B and 18 mg ofStereoisomer 866C as white solids.

Characterization of Stereoisomer 866A. LCMS (ES) m/z 421 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 7.65-7.50 (m, 2H), 7.44-7.32 (m, 3H), 7.22 (t,J=8.8 Hz, 2H), 5.13-4.98 (m, 2H), 4.72 (d, J=17.0 Hz, 1H), 4.21 (d,J=15.2 Hz, 1H), 4.09 (d, J=17.0 Hz, 1H), 3.89 (d, J=7.1 Hz, 2H), 2.23(s, 3H), 1.75 (s, 2H). Analytical chiral HPLC RT: 0.90 min (CHIRALPAKIG-3; 0.46 cm×5 cm; 3 micro; MtBE (0.1% DEA):EtOH=70:30 at 1 ml/min).

Characterization of Stereoisomer 866B. LCMS (ES) m/z 421 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 7.66-7.50 (m, 2H), 7.44-7.32 (m, 3H), 7.22 (t,J=8.8 Hz, 2H), 5.09 (d, J=6.5 Hz, 1H), 5.03 (d, J=15.2 Hz, 1H), 4.73 (d,J=17.1 Hz, 1H), 4.21 (d, J=15.1 Hz, 1H), 4.09 (d, J=17.1 Hz, 1H), 3.89(d, J=7.0 Hz, 2H), 2.27-2.17 (m, 3H), 1.74 (s, 2H). Analytical chiralHPLC RT: 1.5 min (CHIRALPAK IG-3; 0.46 cm×5 cm; 3 micro; MtBE (0.1%DEA):EtOH=70:30 at 1 ml/min).

Characterization of Stereoisomer 866C. LCMS (ES) m/z 421 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 7.65-7.49 (m, 2H), 7.44-7.29 (m, 3H), 7.27-7.13 (m,2H), 5.06-4.94 (m, 2H), 4.77 (d, J=17.1 Hz, 1H), 4.32 (d, J=15.2 Hz,1H), 4.19 (s, 1H), 4.08 (d, J=17.1 Hz, 1H), 4.00 (d, J=8.9 Hz, 1H), 2.94(dq, J=9.2, 4.7, 2.8 Hz, 1H), 2.23 (qd, J=8.0, 6.6, 4.7 Hz, 2H), 1.88(td, J=8.8, 4.5 Hz, 2H). Analytical chiral HPLC RT: 0.89 min (CHIRALPAKIG-3; 0.46 cm×5 cm; 3 micro; MtBE (0.1% DEA):EtOH=70:30 at 1 ml/min).

Characterization of Stereoisomer 866D. LCMS (ES) m/z 421 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 7.65-7.50 (m, 2H), 7.44-7.29 (m, 3H), 7.27-7.14 (m,2H), 5.07-4.94 (m, 2H), 4.77 (d, J=17.1 Hz, 1H), 4.32 (d, J=15.2 Hz,1H), 4.18 (d, J=4.8 Hz, 1H), 4.08 (d, J=17.1 Hz, 1H), 4.00 (d, J=8.9 Hz,1H), 2.95 (q, J=7.2 Hz, 1H), 2.23 (qd, J=8.2, 6.6, 4.5 Hz, 2H), 1.87(ddd, J=13.0, 8.9, 4.2 Hz, 2H). Analytical chiral HPLC RT: 1.86 min(CHIRALPAK IG-3; 0.46 cm×5 cm; 3 micro; MtBE (0.1% DEA):EtOH=70:30 at 1ml/min).

The following compounds were prepared by methods analogous to the methoddescribed for Stereoisomers 866A, 866B, 866C, and 866D:

Number HPLC Conditions Q CHIRALPAK IE-3; 0.46 cm × 5 cm; 3 micro;MtBE(0.1% DEA):EtOH = 50:50 at 1 ml/min V CHIRALPAK IG-3; 0.46 cm × 5cm; 3 micro; MtBE(0.1% DEA):EtOH = 70:30 at 1 ml/min W CHIRALPAK IG-3;0.46 cm × 5 cm; 3 micro; MtBE(0.1% DEA):EtOH = 60:40 at 1 ml/min LRMS(ES) Compound No. m/z ¹H NMR 889A M + H = 530.0 (400 MHz, MethyleneChloride-d₂) δ 8.44 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 7.6Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 5.37 (d, J = 15.5 Hz, 1H), 4.74-4.39(m, 2H), 4.21 (d, J = 15.5 Hz, 1H), 3.94 (dd, J = 7.7, 1.6 Hz, 1H), 3.74(p, J = 7.2 Hz, 1H), 3.24-3.19 (m, 3H), 2.56-2.23 (m, 3H), 1.91 (q, J =10.2 Hz, 2H). 889B M + H = 530.0 (400 MHz, Methylene Chloride-d₂) δ 8.44(d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H),7.45 (d, J = 7.9 Hz, 2H), 5.36 (d, J = 15.6 Hz, 1H), 4.69-4.45 (m, 2H),4.25 (d, J = 15.7 Hz, 1H), 3.99-3.89 (m, 2H), 3.23 (s, 3H), 3.05 (h, J =8.4 Hz, 1H), 2.38-2.09 (m, 4H). 890A M + H = 436.1 (400 MHz, MethyleneChloride-d₂) δ 8.34 (d, J = 2.1 Hz, 1H), 7.63 (dd, J = 8.9, 2.1 Hz, 1H),7.36-7.25 (m, 2H), 7.16-7.05 (m, 2H), 5.28 (d, J = 15.2 Hz, 1H),4.69-4.42 (m, 2H), 4.13 (d, J = 15.2 Hz, 1H), 3.97-3.84 (m, 2H), 3.23(s, 3H), 3.11-2.95 (m, 1H), 2.36-2.23 (m, 2H), 2.23-2.07 (m, 2H). 890BM + H = 436.0 (400 MHz, Methylene Chloride-d₂) δ 8.33 (d, J = 2.1 Hz,1H), 7.63 (dd, J = 8.9, 2.1 Hz, 1H), 7.36-7.27 (m, 2H), 7.10 (t, J = 8.7Hz, 2H), 5.28 (d, J = 15.1 Hz, 1H), 4.65-4.43 (m, 2H), 4.12 (d, J = 15.1Hz, 1H), 3.93 (d, J = 7.7 Hz, 1H), 3.73 (tt, J = 7.9, 6.4 Hz, 1H), 3.21(s, 3H), 2.51-2.33 (m, 2H), 2.36-2.23 (m, 1H), 1.96-1.82 (m, 2H). 891AM + H = 468.1 (400 MHz, Methylene Chloride-d₂) δ 8.34 (d, J = 2.1 Hz,1H), 7.64 (dd, J = 8.9, 2.1 Hz, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.41 (d,J = 8.4 Hz, 2H), 6.71 (t, J = 56.4 Hz, 1H), 5.36 (d, J = 15.5 Hz, 1H),4.66-4.46 (m, 2H), 4.22 (d, J = 15.4 Hz, 1H), 3.98-3.85 (m, 2H), 3.23(s, 3H), 3.12-2.92 (m, 1H), 2.54-2.07 (m, 4H). 891B M + H = 468.1 (400MHz, Methylene Chloride-d₂) δ 8.34 (d, J = 2.1 Hz, 1H), 7.64 (dd, J =8.9, 2.1 Hz, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H),6.71 (t, J = 56.4 Hz, 1H), 5.36 (d, J = 15.5 Hz, 1H), 4.66-4.46 (m, 2H),4.22 (d, J = 15.4 Hz, 1H), 3.98-3.85 (m, 2H), 3.23 (s, 3H), 3.12-2.92(m, 1H), 2.54-2.07 (m, 4H). 740A M + H = 472 (300 MHz, DMSO-d₆) δ 8.47(d, J = 2.1 Hz, 1H), 8.24 (dd, J = 9.4, 2.2 Hz, 1H), 7.73 (d, J = 8.0Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 5.12-5.00 (m, 2H), 4.74 (d, J = 17.0Hz, 1H), 4.36 (dd, J = 16.3, 9.8 Hz, 2H), 4.04 (d, J = 7.7 Hz, 1H), 3.86(q, J = 6.6 Hz, 1H), 2.43-2.12 (m, 3H), 1.73 (q, J = 9.4 Hz, 2H). 740BM + H = 472 (300 MHz, DMSO-d6) δ 8.47 (d, J = 2.1 Hz, 1H), 8.25 (dd, J =9.4, 2.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H),5.09-4.97 (m, 2H), 4.78 (d, J = 17.1 Hz, 1H), 4.49 (d, J = 15.7 Hz, 1H),4.35 (d, J = 17.1 Hz, 1H), 4.18 (t, J = 8.7 Hz, 2H), 2.97-2.94 (, m 1H),2.26-2.28 (m, 2H), 1.87 (td, J = 8.8, 4.4 Hz, 2H). 740C M + H = 472 (300MHz, DMSO-d₆) δ 8.47 (d, J = 2.1 Hz, 1H), 8.24 (dd, J = 9.4, 2.1 Hz,1H), 7.73 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 5.11-5.00 (m,2H), 4.74 (d, J = 16.9 Hz, 1H), 4.36 (dd, J = 16.3, 10.0 Hz, 2H), 4.04(d, J = 7.7 Hz, 1H), 3.87 (p, J = 7.1 Hz, 1H), 2.37-2.04 (m, 3H), 1.73(q, J = 9.4 Hz, 2H). 740D M + H = 472 (300 MHz, DMSO-d₆) δ 8.47 (t, J =1.9 Hz, 1H), 8.25 (dt, J = 9.4, 1.8 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H),7.49 (d, J = 7.9 Hz, 2H), 5.09-4.97 (m, 2H), 4.78 (d, J = 17.1 Hz, 1H),4.49 (d, J = 15.7 Hz, 1H), 4.35 (d, J = 17.1 Hz, 1H), 4.24-4.12 (m, 2H),2.95 (d, J = 9.3 Hz, 1H), 2.28-2.17 (m, 2H), 1.94-1.80 (m, 2H). 892A M +H = 422 (300 MHz, Methanol-d₄) δ 8.39 (d, J = 2.1 Hz, 1H), 7.93 (dd, J =9.1, 2.2 Hz, 1H), 7.42-7.30 (m, 2H), 7.17-7.04 (m, 2H), 5.20 (d, J =15.2 Hz, 1H),4.73 (d, J = 17.2 Hz, 1H), 4.46 (d, J = 17.2 Hz, 1H), 4.25(d, J = 15.1 Hz, 1H), 4.01 (dd, J = 26.0, 6.9 Hz, 2H), 2.50-2.26 (m, J =6.5 Hz, 3H), 1.87 (t, J = 7.2 Hz, 2H). 892B M + H = 422 (300 MHz,Methanol-d₄) δ 8.40 (d, J = 2.1 Hz, 1H), 7.94 (dd, J = 9.2, 2.1 Hz, 1H),7.42-7.31 (m, 2H), 7.18-7.04 (m, 2H), 5.16 (d, J = 15.3 Hz, 1H), 4.73(d, J = 17.3 Hz, 1H), 4.49 (d, J = 17.3 Hz, 1H), 4.39-4.24 (m, 2H), 4.03(d, J = 8.7 Hz, 1H), 3.19-3.00 (m, 1H), 2.38 (dtt, J = 13.3, 6.6, 3.1Hz, 2H), 2.15-1.96 (m, 2H). 892C M + H = 422 (300 MHz, Methanol-d₄) δ8.39 (d, J = 2.1 Hz, 1H), 7.94 (dd, J = 9.1, 2.1 Hz, 1H), 7.37 (dd, J =8.7, 5.3 Hz, 2H), 7.12 (t, J = 8.8 Hz, 1H), 5.20 (d, J = 15.2 Hz, 1H),4.74 (d, J = 17.2 Hz, 1H), 4.47 (d, J = 17.2 Hz, 1H), 4.25 (d, J = 15.1Hz, 1H), 4.09-3.92 (m, 2H), 2.39 (dh, J = 14.1, 7.4, 6.9 Hz, 3H),1.94-1.80 (m, 2H). 892D M + H = 422 (300 MHz, Methanol-d₄) δ 8.40 (d, J= 2.1 Hz, 1H), 7.94 (dd, J = 9.2, 2.1 Hz, 1H), 7.42-7.31 (m, 2H),7.18-7.05 (m, 2H), 5.16 (d, J = 15.2 Hz, 1H),4.73 (d, J = 17.3 Hz, 1H),4.49 (d, J = 17.3 Hz, 1H), 4.39-4.24 (m, 2H), 4.03 (d, J = 8.7 Hz, 1H),3.08 (dq, J = 15.5, 8.3, 7.7 Hz, 1H), 2.39 (dtt, J = 12.3, 6.0, 3.3 Hz,2H), 2.05 (dtt, J = 13.1, 8.9, 4.1 Hz, 2H). 893A M + H = 438 (300 MHz,DMSO-d₆) δ 8.48 (d, J = 2.1 Hz, 1H), 8.26 (dd, J = 9.4, 2.1 Hz, 1H),7.44 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 5.09 (d, J = 6.4 Hz,1H), 4.99 (d, J = 15.2 Hz, 1H), 4.73 (d, J = 17.0 Hz, 1H), 4.29 (dd, J =23.0, 16.1 Hz, 2H), 3.98 (d, J = 7.6 Hz, 1H), 3.86 (d, J = 6.7 Hz, 1H),2.21 (dd, J = 15.7, 9.6 Hz, 3H), 1.79-1.67 (m, 2H). 893B M + H = 438(300 MHz, DMSO-d₆) δ 8.48 (d, J = 2.1 Hz, 1H), 8.26 (dd, J = 9.4, 2.1Hz, 1H), 7.48-7.38 (m, 2H), 7.36-7.27 (m, 2H), 5.07-4.90 (m, 2H), 4.77(d, J = 17.1 Hz, 1H), 4.35 (dd, J = 16.3, 8.1 Hz, 2H), 4.19 (q, J = 5.9Hz, 1H), 4.10 (d, J = 9.3 Hz, 1H), 3.06-2.81 (m, 1H), 2.22 (dt, J =12.3, 6.6 Hz, 2H), 1.94-1.77 (m, 2H). 893C M + H = 438 (300 MHz,DMSO-d₆) δ 8.48 (d, J = 2.1 Hz, 1H), 8.25 (dd, J = 9.4, 2.2 Hz, 1H),7.49-7.39 (m, 2H), 7.33 (d, J = 8.4 Hz, 2H), 5.09 (d, J = 6.4 Hz, 1H),4.99 (d, J = 15.3 Hz, 1H), 4.73 (d, J = 17.0 Hz, 1H), 4.33 (d, J = 17.0Hz, 1H), 4.26 (d, J = 15.3 Hz, 1H), 3.98 (d, J = 7.6 Hz, 1H), 3.86 (q, J= 7.0 Hz, 1H), 2.32-2.12 (m, 3H), 1.72 (q, J = 9.0 Hz, 2H). 893D M + H =438 (300 MHz, DMSO-d₆) δ 8.48 (d, J = 2.1 Hz, 1H), 8.26 (dd, J = 9.4,2.2 Hz, 1H), 7.47-7.38 (m, 2H), 7.36-7.27 (m, 2H), 5.03 (d, J = 5.1 Hz,1H), 4.96 (d, J = 15.4 Hz, 1H), 4.77 (d, J = 17.0 Hz, 1H), 4.35 (dd, J =16.3, 8.1 Hz, 2H), 4.23-4.15 (m, 1H), 4.10 (d, J = 9.3 Hz, 1H), 2.96 (d,J = 22.1 Hz, 1H), 2.22 (dt, J = 12.3, 6.5 Hz, 2H), 1.86 (td, J = 11.9,11.2, 4.2 Hz, 2H). 894A M + H = 418 (300 MHz, Methanol-d₄) δ 8.39 (d, J= 2.1 Hz, 1H), 7.92 (dd, J = 9.1, 2.1 Hz, 1H), 7.20 (s, 4H), 5.25 (d, J= 15.1 Hz, 1H), 4.73 (d, J = 17.2 Hz, 1H), 4.46 (d, J = 17.2 Hz, 1H),4.16 (d, J = 15.0 Hz, 1H), 4.10-3.95 (m, 1H), 3.91 (d, J = 7.3 Hz, 1H),2.50-2.35 (m, 3H), 2.34 (s, 3H), 1.88 (t, J = 8.7 Hz, 2H). 894B M + H =418 (300 MHz, Methanol-d₄) δ 8.39 (d, J = 2.1 Hz, 1H), 7.93 (dd, J =9.2, 2.1 Hz, 1H), 7.20 (s, 4H), 5.22 (d, J = 15.1 Hz, 1H), 4.72 (d, J =17.3 Hz, 1H), 4.49 (d, J = 17.3 Hz, 1H), 4.36-4.18 (m, 2H), 3.97 (d, J =8.8 Hz, 1H), 3.09 (q, J = 7.9 Hz, 1H), 2.43-2.35 (m, 2H), 2.34 (s, 3H),2.16-1.95 (m, 2H). 894C M + H = 418 (300 MHz, Methanol-d₄) δ 8.39 (d, J= 2.1 Hz, 1H), 7.92 (dd, J = 9.1, 2.1 Hz, 1H), 7.20 (s, 4H), 5.25 (d, J= 15.0 Hz, 1H), 4.73 (d, J = 17.2 Hz, 1H), 4.46 (d, J = 17.2 Hz, 1H),4.16 (d, J = 15.0 Hz, 1H), 4.03 (t, J = 7.3 Hz, 1H), 3.91 (d, J = 7.3Hz, 1H), 2.49-2.29 (m, 6H), 1.86 (d, J = 8.6 Hz, 2H). 894D M + H = 418(300 MHz, Methanol-d₄) δ 8.39 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 9.1,2.1 Hz, 1H), 7.20 (s, 4H), 5.22 (d, J = 15.1 Hz, 1H), 4.72 (d, J = 17.2Hz, 1H), 4.48 (d, J = 17.3 Hz, 1H), 4.36-4.18 (m, 2H), 3.97 (d, J = 8.7Hz, 1H), 3.09 (h, J = 8.3 Hz, 1H), 2.37 (dt, J = 13.5, 6.8 Hz, 5H),2.16-1.93 (m, 2H). Compound No. Retention Time (min) HPLC Condition 740A0.85 W 740B 0.82 W 740C 1.56 W 740D 2.98 W 892A 0.95 Q 892B 0.98 Q 892C1.49 Q 892D 1.88 Q 893A 1.37 T 893B 1.40 T 893C 2.00 T 893D 2.80 T 894A2.73 V 894B 3.86 V 894C 1.16 V 894D 1.17 V

Example 75: Synthesis of Compound 867 1. Synthesis of Intermediate 75-1

To a solution of 4-fluorophenylmethanamine (355 mg, 2.8 mmol, 1.0 equiv)in 2,2,2-trifluoroethanol (10.0 mL) was added3-(benzyloxy)cyclobutan-1-one (500 mg, 2.8 mmol, 1.0 equiv). Afterstirring at r.t. for 10 min, to this resulting mixture were added4-chloro-2-fluoro-1-isocyanobenzene (1.5 g, unpurified mixture) andchloroacetic acid (266 mg, 2.8 mmol, 1.0 equiv). The resulting mixturewas stirred at r.t. overnight, concentrated under reduced pressure, andpurified silica gel chromatography, eluted with EA/PE (1/5) to afford1.1 g (21%) of3-(benzyloxy)-N-(4-chloro-2-fluorophenyl)-1-(2-chloro-N-(4-fluorobenzyl)acetamido)cyclobutane-1-carboxamide(Intermediate 75-1) as a yellow oil. LRMS (ES) m/z 533 (M+H).

2. Synthesis of Intermediate 75-2

To a solution of3-(benzyloxy)-N-(4-chloro-2-fluorophenyl)-1-(2-chloro-N-(4-fluorobenzyl)acetamido)cyclobutane-1-carboxamide(546 mg, 1.0 mmol, 1.0 equiv) in DMF (8.0 mL) was added K₂CO₃ (285 mg,2.0 mmol, 2.0 equiv). The mixture was stirred at rt for 1 h, dilutedwater (20 mL), and extracted with EA (60 mL) three times. The combinedorganic layers were washed with brine (30 mL) twice, dried over Na₂SO₄,and concentrated under reduced pressure to afford 550 mg of2-(benzyloxy)-8-(4-chloro-2-fluorophenyl)-5-(4-fluorobenzyl)-5,8-diazaspiro[3.5]nonane-6,9-dione(Intermediate 75-2). LRMS (ES) m/z 497 (M+H).

3. Synthesis of Compound 867

To a stirred solution of2-(benzyloxy)-8-(4-chloro-2-fluorophenyl)-5-(4-fluorobenzyl)-5,8-diazaspiro[3.5]nonane-6,9-dione(660 mg, 1.3 mmol, 1.0 equiv) in MeOH (7 mL) and THF (7 mL) was addedPd(OH)₂/C (132 mg) in portions. The mixture was stirred at r.t. for 3 hunder hydrogen (balloon), filtered off the solid, concentrated, andpurified by Prep-HPLC with the following conditions: (SHIMADZU) Column,XBridge Prep C18 OBD Column, 5 um, 30*150 mm;

mobile phase, Water (10 mM

NH₄HCO₃) and ACN (25% gradient up to 50% in 8 min); Detector UV 254 nm)to afford 150 mg (27%) of8-(4-chloro-2-fluorophenyl)-5-(4-fluorobenzyl)-2-hydroxy-5,8-diazaspiro[3.5]nonane-6,9-dione(Compound 867). LRMS (ES) m/z 407 (M+H).

4. Separation of Compound 867 Diastereomers: Diastereomers 867A and 867B

The racemic compound of8-(4-chloro-2-fluorophenyl)-5-(4-fluorobenzyl)-2-hydroxy-5,8-diazaspiro[3.5]nonane-6,9-dione(150 mg, 0.37 mmol, 1.0 equiv) was purified by Chiral-Prep-HPLC with thefollowing conditions: Column, CHIRALPAK IF-3, 2*25 mm, 5 um; mobilephase, Hex (8 mM, NH₃ in MeOH) and EtOH (60/40); Detector, UV254 nm) toafford 89 mg of first eluted peak (Diastereomer 867A) and 31 mg ofsecond eluted peak (Diastereomer 867B) as white solids

Characterization of Diastereomer 867A. LCMS (ES) m/z 407 (M+H). ¹H NMR(NMR (300 MHz, DMSO-d₆) δ 7.67-7.50 (m, 2H), 7.40 (ddd, J=8.6, 2.3, 1.0Hz, 1H), 7.29 (dd, J=8.6, 5.5 Hz, 2H), 7.19 (t, J=8.9 Hz, 2H), 5.30 (d,J=6.2 Hz, 1H), 4.83 (s, 2H), 4.38 (s, 2H), 4.09 (q, J=7.3 Hz, 1H), 2.65(s, 3H), 2.75-2.55 (m, 1H). Analytical chiral HPLC RT: 1.79 min(CHIRALPAK IF-3; 0.46 cm×5 cm; 3 micro; HEX (0.1% DEA):EtOH=60:40 at 1ml/min).

Characterization of Diastereomer 867B. LCMS (ES) m/z 407 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 7.66-7.54 (m, 2H), 7.46-7.37 (m, 1H), 7.31-7.13 (m,4H), 5.32 (d, J=7.0 Hz, 1H), 4.89 (s, 2H), 4.40 (s, 2H), 3.93 (q, J=6.8Hz, 1H), 2.79 (s, 2H), 2.31 (d, J=9.7 Hz, 2H). Analytical chiral HPLCRT: 2.66 min (CHIRALPAK IF-3; 0.46 cm×5 cm; 3 micro; HEX (0.1%DEA):EtOH=60:40 at 1 ml/min).

The following compounds were prepared by methods analogous to the methoddescribed for Diastereomers 867A and 867B:

LRMS (ES) Compound No. m/Z ¹H NMR 764 M + H = 408.0 ¹H NMR (400 MHz,Methylene Chloride-d₂) δ 8.28-8.20 (m, 1H), 7.60-7.50 (m, 1H), 7.20-7.11(m, 2H), 7.03-6.93 (m, 2H), 4.83 (s, 1H), 4.75 (s, 1H), 4.42 (d, J = 9.1Hz, 2H), 4.29-4.04 (m, 1.5H), 3.22 (s, 0.3H), 2.91 (ddd, J = 10.1, 7.0,3.0 Hz, 1H), 2.86-2.72 (m, 1H), 2.60 (dd, J = 14.9, 3.8 Hz, 1H), 2.31(ddd, J = 10.0, 6.8, 3.0 Hz, 1H), 0.83 (s, 0H). 764A M + H = 408.0 ¹HNMR (400 MHz, DMSO-d₆) δ 8.53 (d, J = 2.1 Hz, 1H), 8.30 (dd, J = 9.5,2.1 Hz, 1H), 7.33-7.24 (m, 2H), 7.22 (t, J = 8.8 Hz, 2H), 5.38 (d, J =6.9 Hz, 1H), 4.93 (s, 2H), 4.56 (s, 2H), 4.04-3.91 (m, 1H), 2.88-2.78(m, 2H), 2.40-2.31 (m, 2H). 764B M + H = 408.0 ¹H NMR (400 MHz, DMSO-d₆)δ 8.53 (d, J = 2.1 Hz, 1H), 8.30 (dd, J = 9.4, 2.1 Hz, 1H), 7.31 (dd, J= 8.5, 5.5 Hz, 2H), 7.22 (t, J = 8.8 Hz, 2H), 4.87 (s, 2H), 4.54 (s,2H), 4.18-4.06 (m, 1H), 3.61 (s, 1H), 2.81-2.70 (m, 2H), 2.69-2.58 (m,2H). 868A M + H = 404.0 ¹H NMR (400 MHz, Methylene Chloride-d₂) δ 8.21(d, J = 2.1 Hz, 1H), 7.52 (dd, J = 9.0, 2.1 Hz, 1H), 7.05 (q, J = 8.1Hz, 4H), 4.79 (s, 2H), 4.38 (s, 2H), 4.23-4.11 (m, 1H), 2.92-2.82 (m,2H), 2.36-2.25 (m, 2H), 2.24 (s, 3H), 1.91 (s, 1H). 868B M + H = 404.0¹H NMR (400 MHz, Methylene Chloride-d₂) δ 8.23 (d, J = 2.0 Hz, 1H), 7.54(dd, J = 8.9, 2.1 Hz, 1H), 7.11-6.98 (m, 4H), 4.72 (s, 2H), 4.40 (s,2H), 4.10 (s, 1H), 3.21 (d, J = 9.7 Hz, 1H), 2.84-2.73 (m, 2H), 2.56(dd, J = 14.8, 3.8 Hz, 2H), 2.24 (s, 3H). 869A M − H = 422 ¹H NMR (300MHz, DMSO-d₆) δ 8.49 (d, J = 2.1 Hz, 1H), 8.27 (dd, J = 9.5, 2.1 Hz,1H), 7.47-7.37 (m, 2H), 7.32-7.22 (m, 2H), 5.35 (d, J = 6.2 Hz, 1H),4.85 (s, 2H), 4.52 (s, 2H), 4.08 (p, J = 7.4 Hz, 1H), 2.78-2.65 (m, 2H),2.65-2.53 (m, 2H). 869B M + H = 424 ¹H NMR (300 MHz, DMSO-d₆) δ 8.50 (d,J = 2.1 Hz, 1H), 8.27 (dd, J = 9.5, 2.2 Hz, 1H), 7.47-7.38 (m, 2H), 7.24(d, J = 8.4 Hz, 2H), 5.36 (d, J = 7.1 Hz, 1H), 4.90 (s, 2H), 4.53 (s,2H), 3.94 (q, J = 6.9 Hz, 1H), 2.79 (t, J = 9.7 Hz, 2H), 2.31 (dd, J =11.3, 8.1 Hz, 2H).

Example 76: Synthesis of Compound 838 1. Synthesis of Intermediate 76-1

To a solution of methyl3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (23.0 g,135.2 mmol, 1.0 equiv) in THF (400.0 mL) at 0° C. was added BH₃-THF (1M/THF, 162 mL, 162 mmol, 1.2 equiv.) dropwise over a period of 1 h. Themixture was stirred at rt overnight, cooled to 0° C., quenched withMeOH, and concentrated under reduced pressure to afford 21 g (99%) ofmethyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate(Intermediate 76-1) as a yellow oil. LRMS (ES) m/z 157 (M+H).

2. Synthesis of Intermediate 76-2

To a stirred solution of methyl3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (15.0 g, 96.0 mmol,1.0 equiv) and imidazole (18.0 g, 264.4 mmol, 2.75 equiv.) in DCM (300.0mL) cooled to 0° C. was added TBSCl (19.0 g, 126.1 mmol, 1.3 equiv.).The mixture was stirred at rt for 1 h, and filtered through celite plug.The filtrate was concentrated under reduced pressure, re-dissolved in EA(300 mL), and added water (300 mL) into the mixture. The aqueous layerwas extract with EA (300 mL). The combined organic layers were washedwith brine (300 mL) twice, dried over Na₂SO₄, concentrated under reducedpressure, and purified by silica gel column chromatography using PE/EA(20/1) as eluent to afford 28 g (86%) of methyl3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate(Intermediate 76-2) as a yellow oil. LRMS (ES) m/z 271 (M+H).

3. Synthesis of Intermediate 76-3

To a solution of methyl3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate(28.0 g, 103.5 mmol, 1.0 equiv) in MeOH (250.0 mL) was added NaOH (4.6g, 115.0 mmol, 1.1 equiv.). The mixture was stirred at 60° C. for 1 h,cooled to rt, acidified to pH 4 with HCl (4 N/water), concentrated underreduced pressure, added water (300 mL) to the mixture, and extractedwith EA (300 mL) twice. The combined organic layer was washed with brine(300 mL) twice, dried over Na₂SO₄, and concentrated under reducedpressure to afford 24 g (90%) of3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylicacid (Intermediate 76-3) as a yellow oil. LRMS (ES) m/z 257 (M+H).

4. Synthesis of Intermediate 76-4

To a solution of3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylicacid (24.0 g, 93.6 mmol, 1.0 equiv) in DCM (400.0 mL) was EDCI (23.3 g,121.7 mmol, 1.3 equiv.). After stirring at rt for 10 min, to the mixturewere added HOBt (2.4 g, 17.8 mmol, 0.19 equiv.), DIEA (38.7 g, 299.5mmol, 3.2 equiv.), and N,O-dimethylhydroxylamine hydrochloride (18.0 g,184.4 mmol, 2.0 equiv.). The mixture was stirred at rt for 2 h, washedwith saturated solution of sodium carbonate (300 mL) once and brine (300mL) twice, dried over Na₂SO₄, and concentrated under reduced pressure toafford 28 g (90% purity) of3-(((tert-butyldimethylsilyl)oxy)methyl)-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide(Intermediate 76-4) as a yellow oil. LRMS (ES) m/z 300 (M+H).

5. Synthesis of Intermediate 76-5

To a solution of3-(((tert-butyldimethylsilyl)oxy)methyl)-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide(28.0 g, 93.5 mmol, 1.0 equiv) in THF (280.0 mL) cooled to 0° C. wasadded phenylmagnesium bromide (3 M. 38 mL, 114 mmol, 1.22 equiv.)dropwise over a period of 30 min under nitrogen atmosphere. The mixturewas stirred at rt for 2 h, cooled to 0° C., quenched with saturatedNH₄Cl solution (300 mL), and extracted with EA (400 mL) twice. Thecombined organic layers were washed with brine (400 mL) twice, driedover Na₂SO₄, concentrated under reduced pressure, and purified by silicagel column chromatography eluting with PE/EA (10/1) to afford 17 g (57%)of(3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)(phenyl)methanone(Intermediate 76-5) as a yellow oil. LRMS (ES) m/z 317 (M+H).

6. Synthesis of Intermediate 76-6

To a solution of(3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)(phenyl)methanone(17.0 g, 53.7 mmol, 1.0 equiv.) in DCM (340.0 mL) was added mCPBA (24.0g, 118.2 mmol, 2.2 equiv., 85% purity). The mixture was stirred at 50°C. for 2 days, cooled to 0° C., quenched with saturated NaHSO₃ solution(200 mL), and extracted with EA (200 mL) twice. The combined organiclayers were washed with saturated sodium carbonate solution (200 mL)once and brine (200 mL) twice, dried over Na₂SO₄, and concentrated underreduced pressure to afford 18 g (90% purity, 90%) of3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-ylbenzoate (Intermediate 76-6) as a yellow oil. LRMS (ES) m/z 333 (M+H).

7. Synthesis of Intermediate 76-7

To a solution of3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-ylbenzoate (18.0 g, 54.1 mmol, 1.0 equiv.) in DCM (180.0 mL) was added HCl(4 N/dioxane, 45 mL, 180 mmol). The mixture was stirred was stirred atrt for 2 h, concentrated under reduced pressure, diluted with water (200mL), and extracted with EA (200 mL) twice. The combined organic layerswere washed with brine (200 mL) twice, dried over Na₂SO₄, concentratedunder reduced pressure, and purified by silica gel column chromatographyeluting with PE/EA (3/1) to afford 6.2 g (52%) of3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl benzoate (Intermediate 76-7)as a yellow oil. LRMS (ES) m/z 219 (M+H).

8. Synthesis of Intermediate 76-8

To a solution of 3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl benzoate(6.2 g, 28.4 mmol, 1.0 equiv) in DCM (60.0 mL) at r.t. was added PCC(7.35 g, 34.1 mmol, 1.2 equiv) in portions. The mixture was stirred atrt for 2 h, diluted with ether (120 mL), stirred for 20 min, filteredoff the solid, concentrated under reduced pressure, and purified bysilica gel column chromatography eluting with PE/EA (10/1) to afford 2.7g (65% purity) of 3-formylbicyclo[1.1.1]pentan-1-yl benzoate(Intermediate 76-8) as a yellow solid. LRMS (ES) m/z 217 (M+H).

9. Synthesis of Intermediate 76-9

To a solution of (4-(trifluoromethyl)phenyl)methanamine (221.5 mg, 1.3mmol, 1.1 equiv) in trifluoroethanol (5.0 mL) was added3-formylbicyclo[1.1.1]pentan-1-yl benzoate (420 mg, 1.3 mmol, 1.1 equiv,˜65% purity). After stirring at r.t. for 10 min, to the mixture wereadded 5-chloro-3-fluoro-2-isocyanopyridine (180 mg, 1.15 mmol, 1.0equiv) and chloroacetic acid (119.5 mg, 1.3 mmol, 1.1 equiv). Theresulting mixture was stirred at r.t. overnight, concentrated underreduced pressure, and purified by silica gel column chromatography,eluted with PE/EtOAc (5:1) to afford 640 mg (89%) of3-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-2-oxoethyl)bicyclo[1.1.1]pentan-1-ylbenzoate (Intermediate 76-9) as a yellow oil. LRMS (ES) m/z 624 (M+H).

10. Synthesis of Intermediate 76-10

To a solution of3-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-2-oxoethyl)bicyclo[1.1.1]pentan-1-ylbenzoate (640 mg, 1.0 mmol, 1.0 equiv) in DMF (10.0 mL) was addedpotassium carbonate (283 mg, 2.0 mmol, 2.0 equiv). The resulting mixturewas stirred at r.t. for 30 min, diluted with water (20 mL), andextracted with EA (20 mL) twice. The combined organic layers were washedwith brine (20 mL), dried over Na₂SO₄, and concentrated under reducedpressure to afford 600 mg (99%) of3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)bicyclo[1.1.1]pentan-1-ylbenzoate (Intermediate 76-10) as a brown oil. LRMS (ES) m/z 588 (M+H).

11. Synthesis of Compound 838

To a solution of3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)bicyclo[1.1.1]pentan-1-ylbenzoate (450 mg, 0.77 mmol, 1.0 equiv) in a mixture of MeOH and water(5/1, 12 mL) was added potassium carbonate (105.8 mg, 0.77 mmol, 1.0equiv). The mixture was stirred at r.t. for 1 h, concentrated underreduced pressure, and purified by RP-HPLC using the following condition:Column XBridge Prep OBD C18 3*15 cm, 5 um; mobile phase acetonitrile inwater (10 mM NH₄HCO₃) gradient from 45 to 75% in 8 min; detector, UV254nm to afford 190 mg of1-(5-chloro-3-fluoropyridin-2-yl)-3-(3-hydroxybicyclo[1.1.1]pentan-1-yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(Compound 838) as a white oil. LRMS (ES) m/z 484 (M+H). ¹H NMR (300 MHz,DMSO-d₆) δ 8.49 (d, J=2.1 Hz, 1H), 8.27 (dd, J=9.5, 2.1 Hz, 1H), 7.74(d, J=8.1 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 5.12 (d, J=15.9 Hz, 1H), 4.73(d, J=17.5 Hz, 1H), 4.67 (s, 1H), 4.50 (dd, J=16.8, 8.9 Hz, 2H), 3.58(d, J=16.6 Hz, 1H), 3.43 (s, 1H), 2.51 (s, 1H), 2.48 (s, 1H), 1.36 (s,3H).

12. Separation of Compound 838 Enantiomers: Enantiomers 838A and 838B

The racemic compound1-(5-chloro-3-fluoropyridin-2-yl)-3-(3-hydroxybicyclo[1.1.1]pentan-1-yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione(140 mg) was separated by Chiral HPLC with the following conditions(Column, CHIRALPAK ID-2, 2*25 cm, 5 um; mobile phase, 50% MTBE (10 mMNH₃ in MeOH) in EtOH; flow rate: 13 mL/min; detector, UV 220/254 nm) toafford 60 mg (first eluted peak) of Enantiomer 838A and 60 mg (secondeluted peak) of Enantiomer 838B as white solids.

Characterization of Enantiomer 838A. LCMS (ES) m/z 484 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 8.49 (d, J=2.1 Hz, 1H), 8.27 (dd, J=9.4, 2.2 Hz,1H), 7.74 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 5.12 (d, J=16.0 Hz,1H), 4.73 (d, J=17.6 Hz, 1H), 4.67 (s, 1H), 4.50 (dd, J=16.8, 9.0 Hz,2H), 3.58 (d, J=16.8 Hz, 1H), 3.41 (d, J=16.2 Hz, 1H), 2.63-2.54 (m,1H), 2.45 (d, J=7.7 Hz, 1H), 1.36 (s, 3H). Analytical chiral HPLC RT:0.89 min (CHIRALPAK ID-3; 0.46 cm×5 cm; 3 micro; MtBE (0.1%DEA):EtOH=50:50 at 1 ml/min).

Characterization of Enantiomer 838B. LCMS (ES) m/z 484 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 8.49 (d, J=2.1 Hz, 1H), 8.27 (dd, J=9.4, 2.2 Hz,1H), 7.74 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 5.12 (d, J=16.0 Hz,1H), 4.73 (d, J=17.6 Hz, 1H), 4.67 (s, 1H), 4.50 (dd, J=16.8, 9.0 Hz,2H), 3.58 (d, J=16.8 Hz, 1H), 3.41 (d, J=16.2 Hz, 1H), 2.63-2.54 (m,1H), 2.45 (d, J=7.7 Hz, 1H), 1.36 (s, 3H). Analytical chiral HPLC RT:1.75 min (CHIRALPAK ID-3; 0.46 cm×5 cm; 3 micro; MtBE (0.1%DEA):EtOH=50:50 at 1 ml/min).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 838:

Compound No. LRMS (ES) m/z 841 M + H = 450 844 M + H = 434 849 M + H =466 852 M + H = 430

The following compounds were prepared by methods analogous to the methoddescribed for Enantiomers 838A and 838B:

HPLC Separation Conditions Number HPLC Conditions X CHIRALPAK ID-3; 0.46cm × 5 cm; 3 micro; MtBE(0.1% DEA):EtOH = 50:50 at 1 ml/min Y CHIRALPAKIA-3; 0.46 cm × 5 cm; 3 micro; MtBE(0.1% DEA):EtOH = 50:50 at 1 ZCHIRALPAK IE-3; 0.46 cm × 5 cm; 3 micro; (Hex:DCM = 3:1)(0.1% DEA):EtOH= 50:50 at 1 ml/min HPLC Enantiomer LRMS (ES) Retention Separation No.m/z Time (min) Conditions 841A M + H = 450 1.06 X 841B M + H = 450 2.38X 844A M + H = 434 1.46 Y 844B M + H = 434 2.27 Y 849A M + H = 466 1.60Z 849B M + H = 466 2.32 Z 852A M + H = 430 1.58 Y 852B M + H = 430 2.11Y

Example 77: Synthesis of Intermediate 77-2(5-chloro-3-fluoro-2-isocyanopyridine 1. Synthesis of Intermediate 77-1

A mixture of Ac₂O (280 g, 2.74 mol, 4.0 equiv) and formic acid (140 g,3.43 mol, 4.5 equiv.) was stirred at 55° C. for 2 h. To the mixturecooled to 0° C. was added 5-chloro-3-fluoropyridin-2-amine (100 g, 682mmol, 1.0 equiv.) dropwise. The mixture was stirred for 2 h at rt,concentrated under reduced pressure, and triturated with Et₂O to afford100 g (84%) of N-(5-chloro-3-fluoropyridin-2-yl)formamide (Intermediate77-1) as a white solid. LRMS (ES) m/z 175 (M+H). ¹H NMR (400 MHz,DMSO-d₆) δ 10.90 (s, 1H), 9.16 (s, 1H), 8.24 (s, 1H), 8.11 (dd, J=10.1,2.1 Hz, 1H).

2. Synthesis of Intermediate 77-2

To a stirred solution of N-(5-chloro-3-fluoropyridin-2-yl)formamide (40g) and TEA (140.1 g, 1.38 mol, 6 equiv.) in DCM (400 mL) cooled to −78°C. was added POCl₃ (40.4 g, 263.5 mmol, 1.15 equiv.) in DCM (100 mL)dropwise. The mixture was stirred at rt overnight, cooled to 0° C.,quenched with MeOH (32 mL), concentrated under reduced pressure, andpurified by silica gel using PE/EA (10/1) as eluent to afford 11 g (31%)of 5-chloro-3-fluoro-2-isocyanopyridine (Intermediate 77-2) as a yellowsolid. LRMS (ES) m/z 156 (M+H).

Example 78: Synthesis of Compound 202 1. Synthesis of Intermediate 78-1

A mixture of Ac₂O (500 mL) and FA (200 mL) was stirred at 60° C. for 2 hand cooled to rt. To the mixture was added 4-amino-3-fluorobenzonitrile(120.0 g, 0.88 mol, 1.0 equiv). The mixture was stirred for 2 h at roomtemperature and concentrated under reduced pressure. The solid wastriturated with Et₂O (2 L) to give 124 g ofN-(4-cyano-2-fluorophenyl)formamide (Intermediate 78-1) as a whitesolid.

2. Synthesis of Intermediate 78-2

To a solution of N-(4-cyano-2-fluorophenyl)formamide (70.0 g, 426.5mmol, 1.0 equiv) in DCM (800 mL) cooled to 0° C. were added TEA (135 g,1334.8 mmol, 3.1 equiv) and a solution of triphosgene (54.4 g, 183.4mmol, 0.43 equiv) in DCM (300 mL) dropwise over a period of 30 min. Themixture was stirred at room temperature overnight, cooled to 0° C.,quenched with MeOH (200 mL), concentrated under reduced pressure, andpurified by silica gel column chromatography, eluted with PE/DCM (5/1)to afford 54 g (87%) of 3-fluoro-4-isocyanobenzonitrile (Intermediate78-2) as a yellow solid.

3. Synthesis of Intermediate 78-3

To a solution of 1-[4-(trifluoromethyl)phenyl]methanamine (71.2 g, 406.5mmol, 1.1 equiv) in trifluoroethanol (1 L) was added tert-butyl3-oxoazetidine-1-carboxylate (69.6 g, 406.5 mmol, 1.1 equiv)). Afterstirring at r.t. for 10 min, to the mixture was added3-fluoro-4-isocyanobenzonitrile (54 g, 369.5 mmol, 1.0 equiv) andchloroacetic acid (38.4 g, 406.5 mmol, 1.1 equiv). The resulting mixturewas stirred at r.t. overnight, concentrated under reduced pressure, andtriturated with MeOH (500 mL) to afford 113 g (54%) of tert-butyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-3-((4-cyano-2-fluorophenyl)carbamoyl)azetidine-1-carboxylate(Intermediate 78-3) as a yellow solid.

4. Synthesis of Intermediate 78-4

To a solution of tert-butyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-3-((4-cyano-2-fluorophenyl)carbamoyl)azetidine-1-carboxylate(113 g, 210 mmol, 1.0 equiv) in DMF (550 mL) was added K₂CO₃ (88 g, 630mmol, 3.0 equiv). The resulting mixture was stirred for 30 min at 60° C.under argon atmosphere, cooled to room temperature, and diluted withwater (1000 mL). The precipitates were collected by filtration and driedby oven below 45° C. to afford 106 g (95%) of tert-butyl8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(Intermediate 78-4) as a white solid.

5. Synthesis of Intermediate 78-5

To a solution of tert-butyl8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-2-carboxylate(106 g, 200 mmol, 1.0 equiv) in DCM (1000 mL) was added2,2,2-trifluoroacetic acid (200 mL) at room temperature. The mixture wasstirred for 2 h at room temperature and concentrated under reducedpressure to afford 106 g (95%) of4-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile2,2,2-trifluoroacetate (Intermediate 78-5) as a brown oil.

5. Synthesis of Compound 202

To a solution of4-(6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile(150 g product described above) in DCM (1000 mL) were added TEA (7 g,69.2 mmol, 3.0 equiv) and acetyl acetate (3.5 g, 34.3 mmol, 1.5 equiv)at 0° C. The mixture was stirred for 4 h at room temperature, washedwith brine (200 mL), dried over anhydrous Na₂SO₄, concentrated underreduced pressure, and purified by reverse phase flash chromatographywith the following conditions: column, C₁₈ silica gel; mobile phase, A:water (10 mM NH₄HCO₃), B: ACN gradient from 35% to 45% (B/A) in 20 min;detector, UV 210/254 nm to afford 75 g (71%) of4-(2-acetyl-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile(Compound 202) as a white solid. LRMS (ES) m/z 475 (M+H). ¹H NMR (400MHz, Methanol-d₄, ppm) δ 7.83-7.77 (m, 1H), 7.77-7.67 (m, 4H), 7.57 (d,J=8.1 Hz, 2H), 4.86 (s, 2H), 4.75-4.68 (m, 1H), 4.60-4.55 (m, 2H),4.55-4.47 (m, 2H), 4.25 (d, J=11.0 Hz, 1H), 1.87 (s, 3H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 202 as described in Example 78:

Compound No. LRMS (ES) m/z 641 M + H = 514.1 642 M + H = 480 643 M + H =499 644 M + H = 465 653 M + H = 495.1 785 M + H = 434 825 M + H = 525.0826 M + H = 507.1 827 M + H = 475.1 828 M + H = 461.0 829 M + H = 371.1830 M + H = 457.1 831 M + H = 493.0 832 M + H = 379.0

Example 79: Synthesis of Compound 835 1. Synthesis of Intermediate 79-1

To a solution of methyl3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (2.0 g, 12.81 mmol,1.0 equiv) in DCM (68.0 mL) at r.t. were added PCC (4.1 g, 19.21 mmol,1.5 equiv) in portions. The mixture was stirred at rt for 2 h, dilutedwith ether (180 mL), stirred for 20 min, filtered off the solid,concentrated under reduced pressure to afford 1.9 g (96%) of methyl3-formylbicyclo[1.1.1]pentane-1-carboxylate (Intermediate 79-1) as abrown solid.

2. Synthesis of Intermediate 79-2

To a solution of (4-chlorophenyl)methanamine (498 mg, 3.5 mmol, 1.1equiv) in trifluoroethanol (5.0 mL) was added methyl3-formylbicyclo[1.1.1]pentane-1-carboxylate (541 mg, 3.5 mmol, 1.1equiv). After stirring at r.t. for 10 min, to the mixture was added5-chloro-3-fluoro-2-isocyanopyridine (500 mg, 1.0 equiv) andchloroacetic acid (332 mg, 3.5 mmol, 1.1 equiv). The resulting mixturewas stirred at rt overnight, concentrated under reduced pressure, andpurified by silica gel column chromatography, eluted with PE/EtOAc (3:1)to afford 600 mg (36%) of methyl3-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-(2-chloro-N-(4-chlorobenzyl)acetamido)-2-oxoethyl)bicyclo[1.1.1]pentane-1-carboxylate(Intermediate 79-2) as a yellow oil. LRMS (ES) m/z 528 (M+H).

3. Synthesis of Intermediate 79-3

To a solution of methyl3-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-(2-chloro-N-(4-chlorobenzyl)acetamido)-2-oxoethyl)bicyclo[1.1.1]pentane-1-carboxylate(580 mg, 1.1 mmol, 1.0 equiv) in DMF (6.0 mL) was added potassiumcarbonate (305 mg, 2.2 mmol, 2.0 equiv). The resulting mixture wasstirred at r.t. for 1 h and filtered. The filtrate was concentratedunder reduced pressure, re-dissolved in EA (20 mL), washed with brine(10 mL) twice, dried over Na₂SO₄, and concentrated under reducedpressure to afford 500 mg (93%) of methyl3-(4-(5-chloro-3-fluoropyridin-2-yl)-1-(4-chlorobenzyl)-3,6-dioxopiperazin-2-yl)bicyclo[1.1.1]pentane-1-carboxylate(Intermediate 79-3) as a brown oil. LRMS (ES) m/z 492 (M+H).

4. Synthesis of Compound 835

A solution of methyl3-(4-(5-chloro-3-fluoropyridin-2-yl)-1-(4-chlorobenzyl)-3,6-dioxopiperazin-2-yl)bicyclo[1.1.1]pentane-1-carboxylate(490 mg, 1.0 mmol, 1.0 equiv) in NH₃ solution (7 N in MeOH) was stirredat r.t. for 3, concentrated under reduced pressure, and purified byRP-HPLC using the following condition: C₁₈ silica gel; mobile phaseacetonitrile in water (both with 0.5% NH₄HCO₃) gradient from 40 to 50%in 10 min; detector, UV254 nm to afford 350 mg (74%) of3-(4-(5-chloro-3-fluoropyridin-2-yl)-1-(4-chlorobenzyl)-3,6-dioxopiperazin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide(Compound 835) as a brown oil. LRMS (ES) m/z 477 (M+H). ¹H NMR (400 MHz,DMSO-d₆) δ 8.50 (d, J=2.1 Hz, 1H), 8.29 (dd, J=9.4, 2.1 Hz, 1H),7.49-7.41 (m, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.31 (s, 1H), 7.00 (s, 1H),5.05 (d, J=15.1 Hz, 1H), 4.58 (d, J=17.3 Hz, 1H), 4.39 (d, J=17.3 Hz,1H), 4.26 (s, 1H), 4.12 (d, J=15.0 Hz, 1H), 1.94 (qd, J=9.5, 1.6 Hz,6H).

The following compounds were prepared by methods analogous to the methoddescribed for Compound 835:

LRMS (ES) Compound No. m/z 778 M + H = 528.1 779 M + H = 508.0 780 M + H= 476.0 781 M + H = 472.1 782 M + H = 540.0 783 M + H = 511.0 790 M + H= 493.0 791 M + H = 461.1 792 M + H = 457.0

5. Separation of Compound 835 Enantiomers: Enantiomers 835A and 835B

The racemic compound of3-(4-(5-chloro-3-fluoropyridin-2-yl)-1-(4-chlorobenzyl)-3,6-dioxopiperazin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide(270 mg) was separated by Chiral HPLC with the following conditions(Column, CHIRALPAK IF, 2*25 cm, 5 um; mobile phase, 50% MTBE (10 mM NH₃in MeOH) in EtOH; flow rate: 13 mL/min; detector, UV 220/254 nm) toafford 123 mg (first eluted peak) of Enantiomer 835A and 123 mg (secondeluted peak) of Enantiomer 835B as white solids.

Characterization of Enantiomer 835A. LCMS (ES) m/z 477 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 8.48 (d, J=2.1 Hz, 1H), 8.27 (dd, J=9.4, 2.2 Hz,1H), 7.44 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.28 (s, 1H), 6.97(s, 1H), 5.04 (d, J=15.1 Hz, 1H), 4.56 (d, J=17.3 Hz, 1H), 4.37 (d,J=17.4 Hz, 1H), 4.25 (s, 1H), 4.11 (d, J=15.0 Hz, 1H), 1.99-1.85 (m,6H). Analytical chiral HPLC RT: 1.09 min (CHIRALPAK IF-3; 0.46 cm×5 cm;3 micro; MtBE (0.1% DEA):EtOH=50:50 at 1 ml/min).

Characterization of Enantiomer 835B. LCMS (ES) m/z 477 (M+H). ¹H NMR(300 MHz, DMSO-d₆) δ 8.48 (d, J=2.1 Hz, 1H), 8.27 (dd, J=9.4, 2.1 Hz,1H), 7.43 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.28 (s, 1H), 6.97(s, 1H), 5.04 (d, J=15.1 Hz, 1H), 4.56 (d, J=17.2 Hz, 1H), 4.37 (d,J=17.3 Hz, 1H), 4.24 (s, 1H), 4.10 (d, J=15.1 Hz, 1H), 1.99-1.85 (m,6H). Analytical chiral HPLC RT: 1.82 min (CHIRALPAK IF-3; 0.46 cm×5 cm;3 micro; MtBE (0.1% DEA):EtOH=50:50 at 1 ml/min).

The following compounds were prepared by methods analogous to the methoddescribed for Enantiomers 835A and 835B:

Number HPLC Conditions J CHIRALPAK ID-3; 0.46 cm × 5 cm; 3 micro;Hex(0.1% DEA):EtOH = 50:50 at 1 ml/min AA CHIRALPAK IE-3; 0.46 cm × 5cm; 3 micro; MtBE(0.1% DEA):EtOH = 60:40 at 1 ml/min BB CHIRALPAK IE-3;0.46 cm × 5 cm; 3 micro; (Hex:DCM = 3:1)(0.1% DEA):EtOH = 70:30 at 1ml/min HPLC Enantiomer LRMS (ES) Retention Separation No. m/z Time (min)Conditions 783A M + H = 511 1.01 AA 783B M + H = 511 1.37 AA 791A M + H= 461 2.15 J 791B M + H = 461 3.13 J 790A M + H = 493 2.03 BB 790B M + H= 493 2.53 BB 792A M + H = 457 1.19 AA 792B M + H = 457 1.64 AA

Biological Example B-1: Myofibril Assay

To evaluate the effect of compounds on the ATPase activity offull-length cardiac myosin in the context of the native sarcomere,skinned myofibril assays were performed. Bovine cardiac myofibrils wereobtained by homogenizing bovine cardiac left ventricular tissue in thepresence of a detergent such as triton X-100. Such treatment removesmembranes and a majority of the soluble cytoplasmic proteins but leavesintact the cardiac sarcomeric acto-myosin apparatus. Myofibrilpreparations retain the ability to hydrolyze ATP in a Ca²⁺ regulatedmanner. ATPase activities of such myofibril preparations in the presenceand absence of compounds were assayed at Ca²⁺ concentrations activatingto a defined fraction of the maximal rate (i.e., 25%, 75%). Smallmolecule agents were assessed for their ability to inhibit thesteady-state ATPase activity of bovine cardiac myofibrils using pyruvatekinase and lactate dehydrogenase (PK/LDH)-coupled enzyme system. Thisassay regenerates myosin-produced ADP into ATP by oxidizing NADH,producing an absorbance change at 340 nm. Prior to testing smallmolecule agents, the bovine cardiac myofibrils were assessed for theircalcium responsiveness and the calcium concentration that achieveseither a 50% (pCa₅₀) or 75% (pCa₇₅) activation of the myofibril systemwas chosen as the final condition for assessing the inhibitory activityof the small molecule agents. All enzymatic activity was measured in abuffered solution containing 12 mM PIPES(piperazine-N,N′-bis(2-ethanesulfonic acid), 2 mM magnesium chloride atpH 6.8 (PM 12 buffer). Final assay conditions were 1 mg/mL of bovinecardiac myofibrils, 4 U/mL pyruvate kinase, 6 U/mL lactatedehydrogenase, 50 μM ATP, 0.1 mg/mL BSA (bovine serum albumin), 10 ppmantifoam, 1 mM DTT, 0.5 mM NADH, 1.5 mM PEP, 0.6 mM EGTA, and an amountof CaCl₂ sufficient to achieve either 50% or 75% activation of themyofibril ATPase activity. Results for compounds tested are provided inTable A. Compounds tested were prepared in accordance with the syntheticprocedures described herein.

TABLE A Cmpd CDMF75 No. IC₁₅ (μM)  1 9.5  2 1.8  3 1.7  4 2.5  5 1.9  60.9  7 1.9  8 3.3  9 2.4  10 5.2  11 17.4  12 6.6  13 7.1  14 6.0  152.7  16 2.7  17 1.7  18 3.1  19 5.7  20 7.5  21 2.6  22 4.1  23 2.2  245.7  25 8.8  26 3.0  27 8.6  28 3.1  29 5.6  30 21.1  31 2.7  32 9.6  335.4  34 10.4  35 14.6  36 24.5  37 6.0  38 12.4  39 3.9  40 7.2  41 7.0 42 5.4  43 3.3  44 2.4  45 12.8  46 0.9  47 3.7  48 1.6  49 9.3  50 5.8 51 5.7  52 17.8  53 14.7  54 7.8  55 6.7  56 18.3  57 33.3  58 4.1  5923.4  60 14.3  61 22.9  62 1.8  63 5.1  64 23.6  65 9.8  66 17.6  67 6.0 68 9.2  69 15.4  70 9.5  71 4.8  72 9.0  73 5.7  74 4.2  75 1.1  76 2.2 77 13.0  78 4.1  79 3.8  80 1.7  81 1.4  82 8.1  83 1.3  84 4.0  8514.3  86 8.6  87 1.9  88 4.0  89 3.3  90 1.7  91 1.1  92 1.0  93 19.7 94 36.1  95 5.0  96 4.5  97 3.1  98 2.4 107 12.7 108 9.4 109 8.3 11034.4 111 19.8 112 33.0 113 18.5 114 7.9 115 10.2 116 7.2 117 16.6 11814.0 119 10.8 120 18.3 121 9.9 122 20.5 123 11.2 127 0.8 128 0.8 129 4.6138 7.0 139 14.8 140 4.4 141 10.7 142 0.8 145 3.8 146 1.2 147 8.1 1482.3 149 8.9 150 1.1 151 12.2 152 2.8 153 6.4 154 19.8 155 0.6 156 7.1157 5.5 158 9.7 159 3.2 160 7.1 161 4.7 162 0.4 163 7.3 164 1.6 165 1.4166 2.4 167 1.3 168 0.3 169 0.2 170 2.9 171 2.0 172 18.5 173 0.6 174 8.0175 1.2 176 8.5 177 1.8 178 0.8 179 0.3 180 1.6 181 6.2 182 2.9 183 4.6184 25.5 185 3.2 186 15.8 187 15.9 188 2.6 189 1.4 190 4.0 191 14.3 1920.6 193 1.7 194 0.4 195 0.4 196 0.4 197 2.7 198 0.5 199 2.3 200 0.9 2015.1 202 0.8 203 0.6 204 0.2 205 0.7 206 0.5 207 4.8 208 3.6 209 0.5 2101.7 211 0.4 212 0.9 213 0.4 214 0.5 215 1.3 216 0.3 217 0.9 218 0.4 2190.4 220 0.8 221 4.1 222 0.7 223 2.3 224 12.1 225 29.6 249B 0.2 266 0.7269 1.2 270 1.9 271 0.6 272 0.5 273 1.8 274 1.0 275 6.0 276 3.0 277 32.7278 0.5 279 1.2 280 0.9 281 4.3 281A 1.7 281B 11.8 282 3.8 283 0.6 2840.5 285 8.3 286 0.7 287 3.2 288 1.8 288A 0.8 288B >39 293 36.0 293A >39293B 15.4 294 33.3 297 11.6 297A 6.5 297B >39 298 5.4 299 7.0 300 28.3301 18.6 302 15.2 303 3.7 304 16.4 305 6.0 306 27.0 307 36.7 308 22.7309 2.8 310 13.1 311 5.9 312 4.9 313 3.9 314 8.4 315 28.9 316 14.3 3172.3 318 7.3 319 24.0 320 17.8 321 22.1 322 10.8 323 6.4 324 11.5 32522.8 326 23.7 327 9.8 328 19.3 329 9.3 330 10.7 331 30.9 332 16.6 33316.6 334 8.0 335 12.2 336 1.1 337 1.63 338 1.51 339 0.5 340 0.7 341 5.4347 26.4 348 0.7 349 0.9 350 5.5 351A >39 351B 2.3 353A >39 353B 2.0355A 0.5 355B >39 357A 0.6 357B >39 359A >39 359B 1.7 361A >39 361B 2.1363A >39 363B 0.8 365A >39 365B 2.1 367A 8.8 367B >39 369A 8.5 369B >39371A 8.2 371B >39 373A 0.4 373B >39 375A >39 375B 0.4 377A >39 377B 2.8379A 4.8 379B >39 381A 6.7 381B >39 383 >39 383A 18.0 383B >39 385 >39385A 20.1 385B >39 387 >39 387A 24.2 387B >39 389A 3.1 389B 22.3 429A33.1 429B 0.2 430B 0.4 432B 0.5 434B 0.4 436B 0.3 438B 0.4 440B 0.2 442B0.4 444B 0.2 446B 0.9 448B 0.8 450B 0.3 452B 0.3 454B 0.1 456B 0.3 5480.6 458B 0.4 459 4.5 462A 0.2 462B 0.4 463B 0.4 465B 0.3 467B 0.8 469B0.6 473B 0.2 475B 0.6 477B 0.4 479B 2.8 481B 3.7 483A 0.4 483B 0.7 484A0.5 484B 0.6 485A 2.1 485B 0.7 486A 12.7 486B 0.7 487A 3.2 487B 0.61488B 0.2 492B 0.4 494B 0.4 496A >39 496B 17.7 498B 29.8 500B 35.5 502B15.2 504A 21.9 528 2.9 529 5.5 530 4.7 531 5.0 532 0.2 533 0.3 534 0.2535 0.3 536 0.2 537 0.3 538 0.2 539 0.2 540 0.2 541 0.2 542 0.2 543 0.3544 0.3 545 0.2 546 1.0 547 0.4 550 0.8 551 2.48 552 0.5 553 1.4 554 0.4555 0.9 556 2.7 558 7.04 559 25.1 560 8.6 561 19.8 562 29.0 563 2.2 56413.0 565 17.8 566 4.0 567 1.2 568 1.2 569 2.6 570 2.2 571 2.0 572 7.4573 6.5 573A 2.5 573B >39 574 0.3 575 1.5 576 2.2 577 0.9 592 1.3 5932.3 610 1.7 612 13.6 612A 6.27 612B >39 615 1.3 616 11.85 619 14.7 6201.8 623 3.0 624 2.0 625 14.5 626 >39 629 32.4 630 18.7 630A 9.7 630B >39631 17.3 632 31.7 633 1.3 633A 0.7 633B 5.0 636 1.3 636A 0.6 636B >39639 1.4 639A 1.0 639B >39 640 1.6 640A 0.9 640B >39 641 12.2 642 10.9643 5.8 643A 3.2 644 6.8 644A 3.2 645 5.8 645A 3.3 646 3.3 646A 1.4646B >39 647 2.1 647A 1.2 647B 28.0 648 2.0 648A 0.8 648B 8.1 649 2.9649A 1.5 649B 7.3 650 2.5 650A 1.7 650B 10.1 651 7.3 652 9.0 653 19.9654 5.3 654A 2.9 654B 38.8 655 7.0 656 9.9 657 1.4 657A 0.7 657B >39 6600.84 661 17.0 662 16.4 663 7.3 664 2.9 664A 1.7 664B 23.7 665 7.3 6662.3 666A 26.9 666B 1.3 667 1.1 667A 0.9 667B 8.7 668 1.4 668A 0.7 668B8.4 687 6.2 688 3.7 689 27.9 691 27.6 691A 12.06 691B >39 700 3.4 7013.9 702 25.5 703 10.1 703A 4.0 703B 37.2 706 4.5 707 2.9 708 1.4 71124.6 711A 10.1 711B >39 714 12.4 714A 6.8 714B >39 717 7.3 717A 4.0 717B33.2 720 9.2 720A 5.4 720B >39 723 7.1 724 13.8 724A 8.7 724B >39 7273.2 727A 1.5 727B 24.3 730 3.4 730A 1.6 730B 19.1 733 11.8 733A 7.2733B >39 736 2.0 739 2.2 740 2.3 740A 1.1 740B 0.97 740C >39 740D >39747 3.7 747A 1.6 747B 10.8 750 1.0 751 1.3 756 5.0 757 7.2 758 19.4 758A8.3 758B >39 761 16.3 761A 8.4 761B >39 764 1.6 764A 1.4 764B 2.5 7684.3 769 7.9 769A 4.1 769B >39 772 7.7 772A 4.2 772B >39 775 8.0 775A 3.7775B >39 778 2.4 779 2.9 780 3.6 781 4.0 782 3.6 783 3.08 783A 2.35783B >39 784 6.8 785 5.0 790 4.9 791 2.7 791A 1.8 791B >39 792 3.8 7993.9 813 0.4 814 0.8 815 0.7 816 0.9 821 2.1 822 >39 823 2.3 824 >39 8250.7 826 1.26 827 2.68 828 1.37 829 2.19 830 1.75 831 0.53 832 0.48 8351.64 836 1.42 837 >39 838 3.8 838A 2.3 838B >39 841 2.7 841A 1.5842B >39 844 8.6 844A 4.3 844B >39 849 5.7 849B 1.8 849A >39 852 6.5852A 3.1 852B >39 857A 5.3 857B >39 858A 7.79 858B 3.7 858C 2.9 858D 5.2859A 0.6 859B 0.3 860A 0.7 860B 0.2 861A 1.0 861B 5.8 862A 3.2 862B >39863A 0.3 863B >39 864A 6.2 864B >39 865A 10.2 866A 4.4 866B >39 866C 2.3866D >39 867A 2.1 867B 1.7 868A 1.6 868B 3.8 869A 1.04 869B 0.59 870A12.7 870B 0.6 871A 4.2 871B 1.4 872A 0.99 872B 1.3 873A 15.3 873B 0.7874A 4.0 874B 1.1 875A 2.2 875B 3.2 876A 2.7 876B 2.7 877A 1.1 877B 1.1878B 3.4 879B 9.3 880A >39 880B 1.9 881B 9.3 881A >39 882 0.3 883 0.4884 0.5 885 0.5 886 0.7 887 0.9 888A >39 889A 5.9 889B 1.9 890A 18.7890B 5.4 891A 14.6 891B 5.7 892A 3.6 892B 2.9 892C >39 892D >39 893A 1.2893B 1.0 893C >39 893D >39 894A >39 894B >39 894C 3.3 894D 3.0

Biological Example B-2: Myocyte Assays (i) Preparation of Adult CardiacVentricular Rat Myocytes

Adult male Sprague-Dawley rats were anesthetized and the hearts werequickly excised, rinsed and the ascending aorta was cannulated.Continuous retrograde perfusion was initiated on the hearts at aperfusion pressure of 60 cm H₂O. Hearts were first perfused with anominally Ca²⁺-free modified Krebs solution of the followingcomposition: 113 mM NaCl, 4.7 mM KCl, 0.6 mM KH₂PO₄, 0.6 mM Na₂HPO₄, 1.2mM MgSO₄, 12 mM NaHCO₃, 10 mM KHCO₃, 30 mM taurine, 5.5 mM glucose and10 mM Hepes (all Sigma). This medium was not recirculated and wascontinually aerated with a 95% O₂/5% CO₂ mixture. After approximately 3minutes, the heart was perfused with a modified Krebs buffersupplemented with collagenase (Worthington) and 12.5 μM final calciumconcentration. The heart was removed from the cannulae after the heartappeared blanched and soft in appearance. The atria and vessels wereremoved and the ventricles were gently dissected into smaller pieceswith forceps. The tissue was homogenized by repeated pipette triturationand the collagenase reaction was stopped by 10% bovine calf serum (BCS),sedimentation and resuspension in perfusion buffer containing 5% BCS and12.5 uM CaCl₂. Myocytes were made calcium tolerant by stepwise additionof a CaCl₂ solution to a final concentration of 1.2 mM. Cells were thenwashed and resuspended in Tyrode's buffer (137 mM NaCl, 3.7 mM KCl, 0.5mM MgCl, 11 mM glucose, 4 mM Hepes, and 1.2 mM CaCl₂, pH 7.4). Cellswere kept for 60 min at 37° C. prior to initiating experiments and usedwithin 5 hrs of isolation. Preparations of cells were used only if cellsfirst passed QC criteria by demonstrating a contractile response tostandard (>150% of basal) and isoproterenol (ISO; >250% of basal)treatment. Additionally, only cells whose basal contractility wasbetween 3 and 8% were used in subsequent experiments with compounds.

(ii) Adult Ventricular Myocyte Contractility Experiments

Aliquots of myocytes in Tyrode's buffer were placed in perfusionchambers (series 20 RC-27NE; Warner Instruments) complete with heatingplatforms. Myocytes were allowed to attach, the chambers were heated to37° C., and the cells were perfused with 37° C. Tyrode's buffer.Myocytes were field stimulated at 1 Hz in with platinum electrodes (20%above threshold). Only cells that had clear striations and werequiescent prior to pacing were used for contractility experiments. Todetermine basal contractility, myocytes were imaged through a 40×objective. Using a variable frame rate (60-240 Hz) charge-coupled devicecamera, the images were digitized and displayed on a computer screen ata sampling speed of 240 Hz (IonOptix Milton, Mass.). Once cellcontraction was stable over time, test compounds (0.01-15 μM) wereperfused into the chambers on the myocytes for 5 minutes. Contractilityof the myocytes and contraction and relaxation velocities were thenrecorded using edge detection.

(iii) Contractility Analysis

Five or more individual myocytes were tested per compound from two ormore different myocyte preparations. For each cell, twenty or morecontractility transients at basal (defined as 1 min prior to compoundinfusion) and after compound addition (defined as 5 min after startingcompound perfusion), were averaged and compared. These averagetransients were analyzed using the IonWizard software (IonOptix) todetermine changes in diastolic length and fractional shortening.Fractional shortening was calculated as: ((resting length−length at peakcontraction) divided by the resting length). The percent change infractional shortening from baseline was calculated as: ((post-dosefractional shortening/basal fractional shortening)*100). The percentreduction in fractional shortening from baseline was calculated as:(100−percent change in fractional shortening from baseline). Maximumcontraction and relaxation velocities (um/sec) was also determined.Results from individual cells were averaged and the SEM was calculated.

The effect of the compounds on the fractional shortening (FS) of themyocytes is shown in Table B.

TABLE B Compound Concentration % FS (% reduction No (μM) from baseline)± SEM # of cells tested 206 10 95.1 ± 1.6 6 202 5 68.4 ± 9.5 7 373A 1076.6 ± 8.8 5 288A 5 64.4 ± 9.7 6 861A 5  88.0 ± 3.31 5 633A 1  77.5 ±5.26 6 % FS reduction = 100 − (average of each cell (post dose FS/predose FS) × 100)

Biological Example B-3: Echocardiography Assessment of AcutePharmacodynamic Effect in Rat Cardiac Contractility

Assessment of in vivo cardiac function by echocardiography was performedin male Sprague Dawley rats under isoflurane (1-3%) anesthesia. 2-DM-mode images of the left ventricle were acquired in the parasternallong-axis view before, during, and after administration of compounds bycontinuous IV infusion or oral gavage. In vivo fractional shortening wasdetermined by M-mode image analysis with the following calculation:((End diastolic diameter−end systolic diameter)/end diastolicdiameter×100). For continuous IV infusion experiments, three pre-dosebaseline M-mode images were taken at 1 minute intervals prior toinfusion of compound. Compounds were formulated in 50% Propylene Glycol(PG): 16% Captisol: 10% dimethylacetamide (DMA) and delivered via ajugular vein catheter at the rate of 1 mL/kg/h. During infusion, M-modeimages were taken at 5 minute intervals. The infusion was stopped whenfractional shortening reached up to a 60% reduction from baseline. Bloodsamples were taken to determine the plasma concentration of thecompounds. Data were reported as an estimated IC₅₀ value, which is theconcentration at which fractional shortening is 50% of the pre-dosebaseline contractility. The IC₅₀ results are summarized in Table C.

TABLE C IC50 Compound No. (mean ± SD, μM) 150 5.44 ± 0.12 202 3.24 ±0.07

For oral dosing studies, three pre-dose baseline M-Mode images weretaken at 1 minute intervals prior to compound administration. Compoundswere formulated in a 0.5% hydroxypropyl methylcellulose 2910 (HPMC2910): 0.1% Tween 80 suspension and delivered as a single dose (5 mL/kg)by oral gavage. At one and four hours post-dose, rats were lightlyanesthetized for M-mode echocardiography measurement. The compoundeffect on cardiac fractional shortening are presented as a percentreduction of baseline fractional shortening (=100%) in Table D.

TABLE D FS (% reduction from FS (% reduction from baseline) at 1 hCompound Dose (Mean ± baseline) at 4 h (Mean ± No. (mg/kg) SEM) SEM) 2023 21.88 ± 2.66 11.25 ± 5.54 15 51.08 ± 1.93 20.18 ± 3.59 278 3.0 15.8 ±2.0 10.6 ± 5.6 6.0 34.4 ± 3.3 12.2 ± 4.2 484A 2.5 21.4 ± 2.4  6.1 ± 3.05.0 49.7 ± 3.7 14.3 ± 5.3 339 2.5 21.8 ± 2.8  5.8 ± 4.4 5.0 66.2 ± 2.919.9 ± 2.0 179 3.0 33.8 ± 2.6  4.5 ± 4.2 6.0 51.9 ± 4.0 15.0 ± 5.4 877A9.0 12.0 ± 1.9  7.5 ± 1.5 30.0 49.6 ± 4.6 43.3 ± 5.5 861A 10 13.4 ± 1.6 2.0 ± 3.1 100 50.0 ± 4.0 48.8 ± 5.0 650A 10.0  7.0 ± 2.1 −3.2 ± 1.170.0 59.7 ± 3.8 51.8 ± 2.3 633A 20.0 25.2 ± 2.1  1.1 ± 3.5 50.0 54.8 ±1.8 33.0 ± 3.0 646A 37.5 28.4 ± 4.2  6.9 ± 6.0 100 57.5 ± 2.0 35.4 ± 6.4666B 25 10.4 ± 1.3  0.6 ± 3.1 100 53.2 ± 1.1 29.8 ± 3.7

Concurrent with echocardiography measurements, blood samples are takento determine the corresponding compound plasma concentration, which maybe represented as IC₅₀ and IC₁₀ values, which is the concentration atwhich fractional shortening is 50% and 10% of the pre-dose baselinecontractility, respectively.

Biological Example B-4: Longitudinal Echocardiography Assessment ofMouse Model of HCM

Assessment over time of in vivo cardiac function by echocardiography isperformed using a previously reported mouse model of familialhypertrophic cardiomyopathy, which is generated by an arginine toglutamine mutation at residue 403 (R403Q) of the alpha cardiac myosinheavy chain (MHC) gene (Geisterfer-Lowrance et al., Science. 1996 May 3;272(5262):731-4). Cardiac dysfunction, fibrosis, and measures of cardiachypertrophy (including ventricular wall thickness) increase with age inthis mouse model (Geisterfer-Lowrance, supra; Jiang et al., Science.2013, 342(6154):111-4).

R403q mice receive vehicle or test compound formulated in chow for 24weeks. Longitudinal echocardiography measurements are performed every 4weeks. Echocardiography measurements are taken with mice underisoflurane (1-3%) anesthesia. 2-D M-mode images of the left ventricleare acquired in short-axis view. In vivo fractional shortening isdetermined by M-Mode image analysis with the following calculation:((End diastolic diameter−end systolic diameter)/end diastolicdiameter×100).

Biological Example B-5: Fibrosis Reduction in a Rat Model of CardiacHypertrophy

Assessment of fibrosis reduction is performed using Dahl Salt Sensitive(DSS) rats, a previously reported hypertension-induced rat model ofheart failure with preserved ejection fraction (Fillmore et al., MolMed. 2018, 24(1):3; Dahl et al., J Exp Med. 1962, 115:1173-90). DSS ratsfed a high salt diet demonstrate progressive cardiovascular dysfunction,including increased systolic blood pressure, diastolic dysfunction,cardiac hypertrophy, and cardiac fibrosis (Fillmore, supra; Dahl, supra,Sakata et al., J Am Coll Cardiol. 2001 January; 37(1):293-9;Kim-Mitsuyama et al., Hypertens Res. 2004 October; 27(10):771-9).

DSS rats receive vehicle or test compound formulated in low or high saltchow for 6 weeks. Perivascular and interstitial cardiac tissue samplesare imaged and assayed for % cardiac fibrosis.

While the foregoing written description of the compounds, uses, andmethods described herein enables one of ordinary skill to make and usethe compounds, uses, and methods described herein, those of ordinaryskill will understand and appreciate the existence of variations,combinations, and equivalents of the specific embodiment, method, andexamples herein. The compounds, uses, and methods provided herein shouldtherefore not be limited by the above-described embodiments, methods, orexamples, but rather encompasses all embodiments and methods within thescope and spirit of the compounds, uses, and methods provided herein.

All references disclosed herein are incorporated by reference in theirentirety.

The invention claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom the group consisting of substituted or unsubstituted phenyl andsubstituted or unsubstituted pyridyl; R^(2A), R^(2B), R³, and R⁴ aredefined by any one of (i)-(iii): (i) R^(2A) is H or substituted orunsubstituted alkyl; R^(2B) is selected from the group consisting of H,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl; R³ is phenyl substituted with two or moresubstituents, or substituted or unsubstituted pyridyl; and R⁴ is H orsubstituted or unsubstituted alkyl; or (ii) R^(2A) is H or substitutedor unsubstituted alkyl; R^(2B) is substituted or unsubstituted phenyl orsubstituted or unsubstituted pyridyl; R³ is unsubstituted C₂-C₄ alkyl;and R⁴ is H or substituted or unsubstituted alkyl; or (iii) R^(2A) andR^(2B) are taken together with the carbon atom to which they areattached to form G¹, wherein G¹ is a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl, substituted orunsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclylring, each of which is optionally fused to a phenyl ring; R³ is selectedfrom the group consisting of unsubstituted C₂-C₆ alkyl, alkylsubstituted with alkoxy, cyano, or halo, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl; and R⁴ is H or unsubstituted alkyl; and R⁵ isH or substituted or unsubstituted alkyl; wherein, when one or more ofprovisions (a)-(b) apply, then R¹ is substituted or unsubstitutedpyridyl or phenyl substituted with at least one substituent other thanmethyl or methoxy: (a) R^(2A) and R^(2B) are as defined by (i) and R³ isphenyl substituted with two or more substituents; (b) R^(2A) and R³ areas defined by (ii) and R^(2B) is 4-methoxyphenyl.
 2. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R^(2A)is H or substituted or unsubstituted alkyl; R^(2B) is selected from thegroup consisting of H, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl; and R³ is phenyl substitutedwith two or more substituents, or substituted or unsubstituted pyridyl.3. The compound of claim 2, or a pharmaceutically acceptable saltthereof, wherein R³ is phenyl substituted with two or more substituents.4. The compound of claim 2, or a pharmaceutically acceptable saltthereof, wherein R³ is substituted or unsubstituted pyridyl.
 5. Thecompound of claim 2, or a pharmaceutically acceptable salt thereof,wherein R³ is phenyl substituted with two or more halo substituentsselected from the group consisting of F and Cl.
 6. The compound of claim5, or a pharmaceutically acceptable salt thereof, wherein R³ is furthersubstituted with one, two, or three —CN substituents.
 7. The compound ofclaim 2, or a pharmaceutically acceptable salt thereof, wherein R^(2A)is substituted or unsubstituted alkyl.
 8. The compound of claim 2, or apharmaceutically acceptable salt thereof, wherein R^(2A) is H.
 9. Thecompound of claim 2, or a pharmaceutically acceptable salt thereof,wherein R^(2B) is substituted or unsubstituted alkyl.
 10. The compoundof claim 2, or a pharmaceutically acceptable salt thereof, whereinR^(2B) is selected from the group consisting of methyl, hydroxymethyl,and isopropyl.
 11. The compound of claim 2, or a pharmaceuticallyacceptable salt thereof, wherein R^(2B) is alkyl substituted withsubstituted or unsubstituted alkoxy.
 12. The compound of claim 2, or apharmaceutically acceptable salt thereof, wherein R^(2B) is alkylsubstituted with substituted or unsubstituted oxetanyl.
 13. The compoundof claim 12, or a pharmaceutically acceptable salt thereof, whereinR^(2B) is methyl substituted with unsubstituted 3-oxetanyl.
 14. Thecompound of claim 2, or a pharmaceutically acceptable salt thereof,wherein R^(2B) is substituted or unsubstituted cycloalkyl.
 15. Thecompound of claim 14, or a pharmaceutically acceptable salt thereof,wherein R^(2B) is cyclobutanyl.
 16. The compound of claim 2, or apharmaceutically acceptable salt thereof, wherein R^(2B) is substitutedor unsubstituted heterocyclyl.
 17. The compound of claim 16, or apharmaceutically acceptable salt thereof, wherein R^(2B) is oxetanyl.18. The compound of claim 17, or a pharmaceutically acceptable saltthereof, wherein R^(2B) is 3-oxetanyl.
 19. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(2A) is H orsubstituted or unsubstituted alkyl; R^(2B) is substituted orunsubstituted phenyl or substituted or unsubstituted pyridyl; and R³ isunsubstituted C₂-C₄ alkyl.
 20. The compound of claim 19, or apharmaceutically acceptable salt thereof, wherein R^(2A) isunsubstituted alkyl.
 21. The compound of claim 19, or a pharmaceuticallyacceptable salt thereof, wherein R^(2A) is H.
 22. The compound of claim19, or a pharmaceutically acceptable salt thereof, wherein R^(2B) issubstituted phenyl or substituted pyridyl.
 23. The compound of claim 19,or a pharmaceutically acceptable salt thereof, wherein R^(2B) is phenylor pyridyl, each of which is substituted with one or more substituentsindependently selected from the group consisting of halo, alkoxy, andsubstituted alkyl.
 24. The compound of claim 19, or a pharmaceuticallyacceptable salt thereof, wherein R^(2B) is phenyl or pyridyl, each ofwhich is substituted with —CF₃.
 25. The compound of claim 19, or apharmaceutically acceptable salt thereof, wherein the R^(2B) is phenylor pyridyl, each of which is substituted with methoxy.
 26. The compoundof claim 19, or a pharmaceutically acceptable salt thereof, wherein R³is isopropyl.
 27. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R^(2A) and R^(2B) are taken togetherwith the carbon atom to which they are attached to form G¹, wherein G¹is a substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl,or substituted or unsubstituted heterocyclyl ring, each of which isoptionally fused to a phenyl ring; and R³ is selected from the groupconsisting of unsubstituted C₂-C₆ alkyl, alkyl substituted with alkoxy,cyano, or halo, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkynyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.
 28. Thecompound of claim 27 or a pharmaceutically acceptable salt thereof,wherein G¹ is selected from the group consisting of substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, andsubstituted or unsubstituted 2,3-dihydro-1H-indene.
 29. The compound ofclaim 27, or a pharmaceutically acceptable salt thereof, wherein G¹ is asubstituted or unsubstituted cycloalkyl or heterocyclyl selected fromthe group consisting of:

wherein * indicates the point of attachment to the parent structure. 30.The compound of claim 27, or a pharmaceutically acceptable salt thereof,wherein G¹ is substituted or unsubstituted


31. The compound of claim 27, or a pharmaceutically acceptable saltthereof, wherein G¹ is substituted with one, two, or three substituentsselected from the group consisting of substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted orunsubstituted acyl, substituted or unsubstituted aminosulfonyl,substituted or unsubstituted aminocarbonylamino, and substituted orunsubstituted alkyl.
 32. The compound of claim 27, or a pharmaceuticallyacceptable salt thereof, wherein G¹ is


33. The compound of claim 27, or a pharmaceutically acceptable saltthereof, wherein R³ is selected from the group consisting ofunsubstituted C₂-C₆ alkyl, alkyl substituted with alkoxy, cyano, orhalo, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, and substituted or unsubstituted aryl. 34.The compound of claim 27, or a pharmaceutically acceptable salt thereof,wherein R³ is phenyl substituted with one or more substituents selectedfrom the group consisting of nitro, alkoxy, halo, cycloalkyl, cyano,alkenyl, alkoxycarbonyl, phenylcarbonyl, and alkyl.
 35. The compound ofclaim 27, or a pharmaceutically acceptable salt thereof, wherein R³ isphenyl substituted with F and CN.
 36. The compound of claim 27, or apharmaceutically acceptable salt thereof, wherein R³ is cycloalkylsubstituted with one or more substituents selected from the groupconsisting of alkyl, cyano, and halo.
 37. The compound of claim 27, or apharmaceutically acceptable salt thereof, wherein R³ is alkylsubstituted with one or more substituents selected from the groupconsisting of alkoxy, cyano, and halo.
 38. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein R⁴ is H.
 39. Thecompound of claim 1 or a pharmaceutically acceptable salt thereof,wherein R⁴ is alkyl substituted with substituted or unsubstitutedalkoxy.
 40. The compound of claim 1 or a pharmaceutically acceptablesalt thereof, wherein R⁵ is H.
 41. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein R¹ is phenyl orpyridinyl, each of which is substituted with one or more substituentsindependently selected from the group consisting of cyano, halo,substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl,and substituted or unsubstituted heterocyclyl.
 42. The compound of claim1 or a pharmaceutically acceptable salt thereof, wherein R¹ is phenylsubstituted with trifluoromethyl.
 43. A compound selected from the groupconsisting of: No. Structure 1

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or a pharmaceutically acceptable salt thereof.
 44. A pharmaceuticalcomposition comprising a compound according to claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 45. A method of treating heart disease in asubject in need thereof, comprising administering to the subject acompound of claim 1, or a pharmaceutically acceptable salt thereof. 46.The method of claim 45, wherein the heart disease is hypertrophiccardiomyopathy.
 47. The method of claim 46, wherein the hypertrophiccardiomyopathy is obstructive or nonobstructive or is caused bysarcomeric and/or non-sarcomeric mutations.
 48. The method of claim 45,wherein the heart disease is heart failure with preserved ejectionfraction.
 49. The method of claim 45, wherein the heart disease isselected from the group consisting of diastolic dysfunction, primary orsecondary restrictive cardiomyopathy, myocardial infarction and anginapectoris, left ventricular outflow tract obstruction, hypertensive heartdisease, congenital heart disease, cardiac ischemia, coronary heartdisease, diabetic heart disease, congestive heart failure, right heartfailure, cardiorenal syndrome, and infiltrative cardiomyopathy.
 50. Themethod of claim 45, wherein the heart disease is or is related to one ormore conditions selected from the group consisting of cardiacsenescence, diastolic dysfunction due to aging, left ventricularhypertrophy and concentric left ventricular remodeling.
 51. A method oftreating a disease or condition associated with hypertrophiccardiomyopathy in a subject in need thereof, comprising administering tothe subject a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 52. The method of claim 51, wherein the disease or condition isselected from the group consisting of Fabry's Disease, Danon Disease,mitochondrial cardiomyopathies, and Noonan Syndrome.
 53. A method oftreating a disease or condition that is associated with secondary leftventricular wall thickening in a subject in need thereof, comprisingadministering to the subject a compound of claim 1, or apharmaceutically acceptable salt thereof.
 54. The method of claim 53,wherein the disease or condition is selected from the group consistingof hypertension, valvular heart diseases, aortic stenosis, Mitral valveregurgitation, metabolic syndromes, diabetes, obesity, end stage renaldisease, scleroderma, sleep apnea, amyloidosis, Fabry's disease,Friedreich Ataxia, Danon disease, Noonan syndrome, and Pompe disease.55. A method of treating a disease or condition that is associated withsmall left ventricular cavity and cavity obliteration, hyperdynamic leftventricular contraction, myocardial ischemia, or cardiac fibrosis in asubject in need thereof, comprising administering to the subject acompound of claim 1, or a pharmaceutically acceptable salt thereof. 56.A method of treating a disease or condition selected from musculardystrophies and glycogen storage diseases in a subject in need thereof,comprising administering to the subject a compound of claim 1, or apharmaceutically acceptable salt thereof.
 57. A method of inhibiting thecardiac sarcomere, comprising contacting the cardiac sarcomere with acompound of claim 1, or a pharmaceutically acceptable salt thereof.